WO2015027206A1 - Methods of treating and preventing endothelial dysfunction using bardoxololone methyl or analogs thereof - Google Patents

Methods of treating and preventing endothelial dysfunction using bardoxololone methyl or analogs thereof Download PDF

Info

Publication number
WO2015027206A1
WO2015027206A1 PCT/US2014/052382 US2014052382W WO2015027206A1 WO 2015027206 A1 WO2015027206 A1 WO 2015027206A1 US 2014052382 W US2014052382 W US 2014052382W WO 2015027206 A1 WO2015027206 A1 WO 2015027206A1
Authority
WO
WIPO (PCT)
Prior art keywords
patient
identified
alkyl
ckd
compound
Prior art date
Application number
PCT/US2014/052382
Other languages
English (en)
French (fr)
Other versions
WO2015027206A8 (en
Inventor
Melanie Pei-Heng CHIN
Colin J. Meyer
Original Assignee
Reata Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA2921386A priority Critical patent/CA2921386A1/en
Priority to CN201480049377.4A priority patent/CN105517554B/zh
Application filed by Reata Pharmaceuticals, Inc. filed Critical Reata Pharmaceuticals, Inc.
Priority to KR1020167006597A priority patent/KR102322057B1/ko
Priority to JP2016536495A priority patent/JP6564372B2/ja
Priority to IL285832A priority patent/IL285832B2/he
Priority to SG11201601202WA priority patent/SG11201601202WA/en
Priority to EA201690456A priority patent/EA201690456A1/ru
Priority to MYPI2016000331A priority patent/MY198522A/en
Priority to EP14789437.2A priority patent/EP3035937A1/en
Priority to MX2016002375A priority patent/MX2016002375A/es
Priority to NZ630951A priority patent/NZ630951A/en
Priority to BR112016003454-6A priority patent/BR112016003454B1/pt
Priority to AU2014308600A priority patent/AU2014308600B2/en
Publication of WO2015027206A1 publication Critical patent/WO2015027206A1/en
Publication of WO2015027206A8 publication Critical patent/WO2015027206A8/en
Priority to IL244171A priority patent/IL244171B/he
Priority to IL272242A priority patent/IL272242B/he
Priority to PH12016500358A priority patent/PH12016500358A1/en
Priority to HK16111185.4A priority patent/HK1223015A1/zh
Priority to AU2020203510A priority patent/AU2020203510B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates generally to the fields of biology and medicine. More particularly, it concerns, in some aspects, methods for treating and/or preventing endothelial dysfunction in patients who are diagnosed with or at risk for cardiovascular disease (including patients diagnosed with or at risk for pulmonary arterial hypertension, other forms of pulmonary hypertension, atherosclerosis, restenosis, hyperlipidemia, hypercholesterolemia, metabolic syndrome, or obesity) and other diseases or conditions using bardoxolone methyl and analogs thereof.
  • cardiovascular disease including patients diagnosed with or at risk for pulmonary arterial hypertension, other forms of pulmonary hypertension, atherosclerosis, restenosis, hyperlipidemia, hypercholesterolemia, metabolic syndrome, or obesity
  • Oxidative stress arises in cells when the production of antioxidant proteins, such as glutathione, catalase, and superoxide dismutase, is inadequate to cope with intracellular or local levels of reactive oxygen or nitrogen species, such as superoxide, hydrogen peroxide, and peroxynitrite.
  • antioxidant proteins such as glutathione, catalase, and superoxide dismutase
  • nitrogen species such as superoxide, hydrogen peroxide, and peroxynitrite.
  • nitric oxide is an important signaling molecule, its excessive production can also contribute to oxidative stress.
  • Inflammation is a biological process that provides resistance to infectious or parasitic organisms and the repair of damaged tissue.
  • Inflammation is commonly characterized by localized vasodilation, redness, swelling, and pain, the recruitment of leukocytes to a site of infection or injury, production of inflammatory cytokines, such as TNF-a and IL-1, and production of reactive oxygen or nitrogen species.
  • tissue remodeling, angiogenesis, and scar formation may occur as part of the wound healing process.
  • the inflammatory response is regulated and temporary, and resolves in an orchestrated fashion once the infection or injury has been dealt with adequately.
  • acute inflammation can become excessive and life-threatening if regulatory mechanisms fail.
  • inflammation can become chronic and cause cumulative tissue damage or systemic complications.
  • Specialized cells activated by proinflammatory signaling pathways can be a significant source of reactive oxygen and nitrogen species, creating or perpetuating oxidative stress in surrounding tissues.
  • Inflammatory cytokines such as TNFa, IL-6, and gamma-interferon, can also stimulate the production of reactive oxygen/nitrogen species in a variety of cells and thereby promote oxidative stress.
  • Endothelial dysfunction the failure of vascular endothelial cells to perform their normal functions, is a common early feature of many cardiovascular diseases and related disorders, including atherosclerosis, hypertension, coronary artery disease, chronic kidney disease, pulmonary hypertension, vascular complications of diabetes, and cardiovascular complications of many chronic diseases. See, e.g., Pepine, 1998.
  • the endothelium (a single layer of cells lining essentially the entire vascular system) regulates the balance between vasoconstriction and vasodilation. It also exerts anticoagulant and antiplatelet properties and provides a physical barrier between the bloodstream and the rest of the body, regulating both cellular trafficking and the passage of fluid into tissue.
  • CECs circulating endothelial cells
  • endothelial dysfunction is impaired endothelium-dependent vasodilation, which is mediated by nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS), a constitutive form of NOS that is principally expressed in endothelial cells (e.g., Davignon, 2004).
  • NO nitric oxide
  • eNOS endothelial nitric oxide synthase
  • cGMP cyclic guanosine monophosphate
  • endothelium e.g., inhibition of platelet aggregation, inhibition of leukocyte adherence, and inhibition of VSMC proliferation
  • NO In dysfunctional endothelium, NO production is impaired.
  • Oxidative stress is a major underlying factor in the development of endothelial dysfunction.
  • Many risk factors associated with cardiovascular disease e.g., hypertension, activation of the renin/angiotensin system, hypercholesterolemia, cigarette smoking, and diabetes
  • OX NADPH oxidases
  • This excess superoxide is a direct source of oxidative stress and also can activate other enzymes that produce reactive oxygen species (e.g., xanthine oxidase; Forstermann, 2006). Excess superoxide can also react with NO to form peroxynitrite, which in turn can oxidize (and deplete) tetrahydrobiopterin (BH4), an essential cofactor for the production of NO by eNOS. When BH4 is depleted, eNOS becomes "uncoupled” and produces superoxide instead of NO, adding to the overall state of oxidative stress (e.g., Forstermann, 2006).
  • BH4 tetrahydrobiopterin
  • Endothelial dysfunction leads to damage of the arterial wall, and is recognized as an early marker for atherosclerosis, occurring before the presence of detectable atherosclerotic plaques (e.g., Davignon, 2004).
  • endothelial dysfunction leads to contraction of VSMC, leading to vasoconstriction and hypertension. More generally, endothelial dysfunction is implicated in disorders involving proliferation of VSMC, including restenosis following vascular surgery and pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • Atherosclerosis the underlying defect leading to many forms of cardiovascular disease, occurs when a physical defect or injury to the lining (endothelium) of an artery triggers endothelial dysfunction and an inflammatory response involving the proliferation of vascular smooth muscle cells and the infiltration of leukocytes into the affected area.
  • a complicated lesion known as an atherosclerotic plaque may form.
  • Such a plaque comprises the above-mentioned cells combined with deposits of cholesterol-bearing lipoproteins and other materials. These plaques can directly interfere with adequate blood circulation or can rupture creating a thrombus (blood clot) that precipitates a heart attack, stroke, or other ischemic event (e.g., Hansson et ah, 2006).
  • cardiovascular disease treatments for cardiovascular disease include preventive treatments, such as the use of drugs intended to lower blood pressure or circulating levels of cholesterol and lipoproteins, as well as treatments designed to reduce the adherent tendencies of platelets and other blood cells (thereby reducing the rate of plaque progression and the risk of thrombus formation). More recently, drugs, such as streptokinase and tissue plasminogen activator, have been introduced and are used to dissolve the thrombus and restore blood flow.
  • Surgical treatments include coronary artery bypass grafting to create an alternative blood supply, balloon angioplasty to compress plaque tissue and increase the diameter of the arterial lumen, and carotid endarterectomy to remove plaque tissue in the carotid artery.
  • Such treatments may be accompanied by the use of stents, expandable mesh tubes designed to support the artery walls in the affected area and keep the vessel open.
  • drug-eluting stents has become common in order to prevent post-surgical restenosis (renarrowing of the artery) in the affected area. Restenosis is primarily driven by proliferation of VSMC triggered by injury-driven inflammatory signaling and endothelial dysfunction.
  • These devices are wire stents coated with a biocompatible polymer matrix containing a drug that inhibits cell proliferation (e.g., paclitaxel or rapamycin). The polymer allows a slow, localized release of the drug in the affected area with minimal exposure of non-target tissues.
  • Pulmonary hypertension is a condition in which elevated pressure is found in the pulmonary artery. Pulmonary hypertension (PH) is defined as a resting mean pulmonary artery pressure greater than 25 mmHg. It can lead to right ventricular hypertrophy and right- sided heart failure if it is not successfully treated. Endothelial dysfunction is commonly implicated in the pathogenesis of PH (e.g., Gologanu et al, 2012; Bolignano et al, 2013; Dumitrascu et al, 2013; Kosmadakis et al, 2013; Guazzi and Galie, 2012). Pulmonary hypertension may arise in relation to a variety of conditions.
  • PH PH associated with left-sided heart disease
  • PH associated with lung diseases such as COPD and/or hypoxia (e.g., from sleep apnea);
  • Pulmonary arterial hypertension (PAH), a particularly serious subtype of pulmonary hypertension (Class 1 in the WHO classification of PH), may in its origin be idiopathic, familial, secondary to congenital heart disease, secondary to connective tissue disease, secondary to portal hypertension and pulmonary veno-occlusive disease, or related to drug or toxin exposure (e.g., Bolignano et al, 2013).
  • PAH is a disease of the small pulmonary arteries that is characterized by excessive vasoconstriction, fibrosis, thrombosis, pulmonary vascular remodeling, and right ventricular hypertrophy (RVH).
  • Endothelial dysfunction is believed to play a key role in the pathogenesis of this disease (e.g., Humbert, 2004, which is incorporated herein by reference in its entirety).
  • PAH results in a progressive increase in pulmonary vascular resistance, which ultimately leads to right ventricular failure and death.
  • PAH does not metastasize or disrupt tissue boundaries, it shares some common features with cancer, including hyperproliferation and resistance to apoptosis of certain cells (e.g., VSMC) as well as glycolytic metabolism of these proliferating cells (analogous to the well-known Warburg effect in cancer).
  • Activation of transcription factors implicated in cancer e.g., NF-kappa B and STAT3 has been reported in PAH (e.g., Paulin et ah, 2012; Hosokawa, 2013).
  • the present invention provides methods for treating and/or preventing endothelial dysfunction in patients who are diagnosed with or at risk for cardiovascular disease (including patients diagnosed with or at risk for pulmonary arterial hypertension, other forms of pulmonary hypertension, atherosclerosis, restenosis, hyperlipidemia, hypercholesterolemia, metabolic syndrome, or obesity) and other diseases or conditions using bardoxolone methyl and analogs thereof.
  • the invention provides methods of treating or preventing endothelial dysfunction in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:
  • Ri is -CN, halo, -CF 3 , or -C(0)R a , wherein R a is -OH, alkoxy (C i-4), -NH 2 , alkylaminO(ci-4), or -NH-S(0)2-alkyl( C i-4);
  • R2 is hydrogen or methyl
  • R3 and R4 are each independently hydrogen, hydroxy, methyl or as defined below when either of these groups is taken together with group R c ;
  • Y is:
  • R c is: hydrogen, hydroxy, halo, amino, -NHOH, , or thio; or alkyl(c ⁇ 8), alkenyl (c ⁇ 8), alkynyl (c ⁇ 8), aryl (c ⁇ 8), aralkyl (C ⁇ s), heteroaryl (c ⁇ 8), heterocycloalkyl(c ⁇ 8), alkoxy(c ⁇ 8i, alkenyloxy(c ⁇ s), aryloxy(c ⁇ 8), aralkoxy(c ⁇ 8), heteroaryloxy(c ⁇ 8), acyloxy(c ⁇ 8), alkylaminO(c ⁇ 8), dialkylaminO(c ⁇ 8), arylaminO(c ⁇ 8), alkylsulfonylaminO(c ⁇ 8), amidO(c ⁇ 8), -NH-alkoxy( C ⁇ 8), -NH-heterocycloal
  • R c and R3, taken together, are -O- or - R ⁇ -, wherein R d is hydrogen or alkyl(c ⁇ 4); or
  • R c and R4, taken together, are -O- or -NRj-, wherein R d is hydrogen or alkyl(c ⁇ 4); or
  • alkyl(c ⁇ 8) alkenyl (c ⁇ 8), alkynyl (C ⁇ 8), aryl (c ⁇ 8), aralkyl (C ⁇ 8), heteroaryl (c ⁇ 8), heterocycloalkyl(c ⁇ 8), alkoxy(c ⁇ s), aryloxy(c ⁇ 8), aralkoxy(c ⁇ s), heteroaryloxy(c ⁇ 8), acyloxy(c ⁇ 8), alkylaminO(c ⁇ 8), dialkylamino(c ⁇ 8), arylamino(c ⁇ 8), or a substituted version of any of these groups; or a pharmaceutically acceptable salt or tautomer thereof,
  • BNP B-type natriuretic peptide
  • the patient has pulmonary arterial hypertension or exhibits one or more symptoms of pulmonary arterial hypertension. In some embodiments, the patient has been identified as not having at least two of the characteristics. In some embodiments, the patient has been identified as not having at least three of the characteristics. In some embodiments, the patient has been identified as not having all four of the characteristics.
  • the compound is CDDO-Me.
  • at least a portion of the CDDO-Me is present as a polymorphic form, wherein the polymorphic form is a crystalline form having an X-ray diffraction pattern (CuKa) comprising significant diffraction peaks at about 8.8, 12.9, 13.4, 14.2 and 17.4 °2 ⁇ .
  • the X-ray diffraction pattern (CuKa) is substantially as shown in FIG. 1A or FIG. IB.
  • the CDDO-Me is present as a polymorphic form, wherein the polymorphic form is an amorphous form having an X-ray diffraction pattern (CuKa) with a halo peak at approximately 13.5 °2 ⁇ , substantially as shown in FIG. 1C, and a T g .
  • the compound is an amorphous form.
  • the compound is a glassy solid form of CDDO-Me, having an X-ray powder diffraction pattern with a halo peak at about 13.5 °2 ⁇ , as shown in FIG. 1C, and a T g .
  • the T g value falls within a range of about 120 °C to about 135 °C. In some variations, the T g value is from about 125 °C to about 130 °C.
  • the compound is administered locally. In some embodiments, the compound is administered systemically. In some embodiments, the compound is administered orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, orally, parenterally, rectally, subconjunctivally, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in cremes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, via localized perfusion, bathing target cells directly
  • the compound is formulated as a hard or soft capsule, a tablet, a syrup, a suspension, a solid dispersion, a wafer, or an elixir.
  • the soft capsule is a gelatin capsule.
  • the compound is formulated as a solid dispersion.
  • the hard capsule, soft capsule, tablet or wafer further comprises a protective coating.
  • the formulated compound comprises an agent that delays absorption.
  • the formulated compound further comprises an agent that enhances solubility or dispersibility.
  • the compound is dispersed in a liposome, an oil-in-water emulsion or a water-in-oil emulsion.
  • the pharmaceutically effective amount is a daily dose from about 0.1 mg to about 500 mg of the compound. In some variations, the daily dose is from about 1 mg to about 300 mg of the compound. In some variations, the daily dose is from about 10 mg to about 200 mg of the compound. In some variations, the daily dose is about 25 mg of the compound. In other variations, the daily dose is about 75 mg of the compound. In still other variations, the daily dose is about 150 mg of the compound. In further variations, the daily dose is from about 0.1 mg to about 30 mg of the compound. In some variations, the daily dose is from about 0.5 mg to about 20 mg of the compound. In some variations, the daily dose is from about 1 mg to about 15 mg of the compound.
  • the daily dose is from about 1 mg to about 10 mg of the compound. In some variations, the daily dose is from about 1 mg to about 5 mg of the compound. In some variations, the daily dose is from about 2.5 mg to about 30 mg of the compound. In some variations, the daily dose is about 2.5 mg of the compound. In other variations, the daily dose is about 5 mg of the compound. In other variations, the daily dose is about 10 mg of the compound. In other variations, the daily dose is about 20 mg of the compound. In still other variations, the daily dose is about 30 mg of the compound.
  • the pharmaceutically effective amount is a daily dose is 0.01 -
  • the daily dose is 0.05 - 20 mg of compound per kg of body weight. In some variations, the daily dose is 0.1 - 10 mg of compound per kg of body weight. In some variations, the daily dose is 0.1 - 5 mg of compound per kg of body weight. In some variations, the daily dose is 0.1 - 2.5 mg of compound per kg of body weight.
  • the pharmaceutically effective amount is administered in a single dose per day. In some embodiments, the pharmaceutically effective amount is administered in two or more doses per day.
  • the subject is a primate.
  • the primate is a human.
  • the subject is a cow, horse, dog, cat, pig, mouse, rat or guinea
  • the compound is substantially free from optical isomers thereof.
  • the compound is in the form of a pharmaceutically acceptable salt. In other variations of the above methods, the compound is not a salt.
  • the compound is formulated as a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a therapeutically effective amount of the compound and (ii) an excipient selected from the group consisting of (A) a carbohydrate, carbohydrate derivative, or carbohydrate polymer, (B) a synthetic organic polymer, (C) an organic acid salt, (D) a protein, polypeptide, or peptide, and (E) a high molecular weight polysaccharide.
  • the excipient is a synthetic organic polymer.
  • the excipient is selected from the group consisting of a hydroxypropyl methyl cellulose, a poly[l-(2-oxo-l- pyrrolidinyl)ethylene or copolymer thereof, and a methacrylic acid - methylmethacrylate copolymer.
  • the excipient is hydroxypropyl methyl cellulose phthalate ester.
  • the excipient is PVP/VA.
  • the excipient is a methacrylic acid - ethyl acrylate copolymer.
  • the methacrylic acid and ethyl acrylate may be present at a ratio of about 1 : 1.
  • the excipient is copovidone.
  • FIGS. 1A-C - X-ray Powder Diffraction (XRPD) Spectra of Forms A and B of RTA 402.
  • FIG. 1A shows unmicronized Form A
  • FIG. IB shows micronized Form A
  • FIG. 1C shows Form B.
  • FIG. 2 Effect of Bardoxolone Methyl on Circulating Endothelial Cells in Diabetic CKD Patients.
  • Values represent mean change on Day 28 (Stratum 1) or 56 (Stratum 2) compared to baseline + SEM. (402-C-0801). ⁇ ⁇ 0.05; * p ⁇ 0.01 vs. baseline. Not all patients in either stratum had both baseline and post-treatment samples available.
  • FIGS. 3A-D Reactive Oxygen Species (ROS) and Nitric Oxide (NO) Levels in Human Endothelial Cells after Treatment with Bardoxolone Methyl (RTA 402) and RTA 403 (CDDO-Im).
  • Confluent human umbilical vein endothelial (HUVEC) cells were treated with the indicated concentrations of bardoxolone methyl or RTA 403 for 48 hours. Toxicity was not observed at the tested concentrations.
  • ROS levels reflect assessment of mitochondrial superoxide using mitoSOX reagent. NO levels were measured using the DAF2-DA assay.
  • AFU arbitrary fluorescence units.
  • FIG. 3A shows ROS levels after treatment with RTA 402.
  • FIG. 3B shows ROS levels after treatment with RTA 403.
  • FIG. 3C shows NO levels after treatment with RTA 402.
  • FIG. 3D shows NO levels after treatment with RTA 403.
  • FIG. 4 Effect of Bardoxolone Methyl Analog on ETA and ETB Receptors in a Rat 5/6 Nephrectomy Model of Pressure-Mediated Chronic Renal Failure (CRF).
  • Bardoxolone methyl analog RTA dh404 suppresses ET A and induces ET B receptors in the kidney of the 5/6 nephrectomy model of pressure-mediated chronic renal failure (CRF) in rats.
  • the bardoxolone methyl analog restores normal ETA levels and partially restores ETB expression, promoting vasodilation.
  • Sprague-Dawley rats were subjected to a sham operation (control) or 5/6 nephrectomy to induce chronic renal failure (CRF).
  • FIGS. 5A-B Effect of Bardoxolone Methyl on ETA Expression in Normal Healthy Non-human Primates. Bardoxolone methyl downregulates ETA receptor expression (— 65%) in normal monkeys; ETA receptor levels returned to vehicle levels after a 14 day recovery period. No differences were observed on ET B receptor expression in monkey kidney after bardoxolone administration. BARD animals were dosed orally for 28 days with 30/mg/kg/day BARD in sesame oil. A subgroup of animals was treated with BARD for 28 days and then allowed to recover for 14 days with no further treatment. ** p ⁇ 0.01 vs. vehicle control. FIG. 5A shows ETA immunohistochemistry. FIG. 5B shows ETA expression densitometry.
  • FIG. 6 Mean eGFR Over Time in BEACON (Safety Population). Mean observed eGFR over time by treatment week in placebo versus bardoxolone methyl patients. Only includes assessments of eGFR collected on or before a patient's last dose of study drug. Visits are derived relative to a patient's first dose of study drug. Data are means ⁇ SE.
  • FIGS. 7A-B Percentage of eGFR Decliners in Bardoxolone Methyl vs. Placebo Patients in BEACON (Safety Population). Percentage of patients with changes in eGFR from baseline of ⁇ -3, ⁇ -5, or ⁇ -7.5 mL/min/1.73 m 2 by treatment week in placebo (FIG. 7A) versus bardoxolone methyl (FIG. 7B) patients. Only includes assessments of eGFR collected on or before a patient's last dose of study drug. Visits are derived relative to a patient's first dose of study drug. Percentages calculated relative to number of patients with available eGFR data at each visit.
  • FIG. 8 Time to Composite Primary Outcome Event in BEACON (ITT Population). Results from a randomized, double-blind, placebo-controlled phase 3 study in T2D patients with Stage 4 CKD (BEACON, RTA402-C-0903). Patients were administered placebo or 20 mg of bardoxolone methyl once daily. Analysis includes only ESRD or cardiovascular (CV) death events occurring on or prior to study drug termination date (October 18, 2012) that were positively adjudicated by an independent Event Adjudication Committee, as outlined in the BEACON EAC Charter.
  • FIG. 9 Time to First Hospitalization for Heart Failure or Death Due to Heart Failure
  • FIG. 10 Overall Survival of Bardoxolone Methyl vs. Placebo Patients in BEACON. Results from a randomized, double-blind, placebo-controlled phase 3 study in T2D patients with Stage 4 CKD (BEACON, RTA402-C-0903). Patients were administered placebo or 20 mg of bardoxolone methyl once daily. Analysis includes all deaths occurring prior to database lock (March 4, 2013). Top line is BARD; bottom line is placebo.
  • FIG. 11 Mean Serum Magnesium Levels in Bardoxolone Methyl vs. Placebo Patients in BEACON. Mean observed serum magnesium levels over time by treatment week in placebo vs. bardoxolone methyl patients. Only includes assessments of serum magnesium collected on or before a patient's last dose of study drug. Visits are derived relative to a patient's first dose of study drug. Data are means ⁇ SE. Top line is placebo; bottom line is bardoxolone methyl.
  • FIGS. 12A-B Changes from Baseline over Time in Systolic (FIG. 12A) and Diastolic (FIG. 12B) Blood Pressure in Bardoxolone Methyl vs. Placebo Patients in BEACON (Safety Population). Data includes only vital assessments collected on or before a patient's last dose of study drug. Visits are derived relative to a patient's first dose of study drug.
  • FIGS. 14A-D Placebo-Corrected Changes from Baseline in Systolic Blood Pressure on Study Days 1 and 6 in Healthy Volunteers Administered Bardoxolone Methyl. Results from a multiple-dose, randomized, double-blind, placebo-controlled thorough QT study in healthy volunteers (RTA402-C-1006). Patients were treated with placebo, 20 mg or 80 mg of bardoxolone methyl, or 400 mg of moxifloxacin (active comparator) once daily for 6 consecutive days. Data are mean changes ( ⁇ SD) from baseline 0-24 hours post-dose on Study Day 1 and Study Day 6.
  • FIG. 14A shows dosing with 20 mg BARD on Study Day 1.
  • FIG. 14B shows dosing with 20 mg BARD on Study Day 6.
  • FIG. 14C shows dosing with 80 mg BARD on Study Day 1.
  • FIG. 14D shows dosing with 80 mg BARD on Study Day 6.
  • FIGS. 15A-B Placebo-Corrected Changes from Baseline in QTcF in Healthy Volunteers Administered Bardoxolone Methyl. Results from a multiple-dose, randomized, double-blind, placebo-controlled thorough QT study in healthy volunteers (RTA402-C-1006). QTcF interval changes in subjects administered bardoxolone methyl (20 mg or 80 mg - FIG. 15A and FIG. 15B, respectively) are shown relative to changes in patients receiving placebo treatment for 6 consecutive days. Data are mean values ⁇ 90% CI, assessed 0-24 hours post- dose on Study Day 6, where the upper limit of the 90% CI is equivalent to the 1 -sided, upper 95% confidence limit. The 10 ms threshold reference line is relevant to the upper confidence limits.
  • FIGS. 16A-B Kaplan-Meier Plots for Fluid Overload Events in ASCEND (FIG.
  • FIG. 16A Heart Failure Events in BEACON (ITT Population; FIG. 16B). Time-to-first event analysis for fluid overload events in ASCEND and heart failure in BEACON. Fluid overload events in ASCEND were taken from the adverse event reports of the local investigators.
  • fluid overload included: heart failure, edema, fluid overload, fluid retention, hypervolemia, dyspnea, pleural and pericardial effusions, ascites, weight increase, pulmonary rales, and pulmonary edema. Analysis includes only heart failure events occurring on or prior to study drug termination date (October 18, 2012) that were positively adjudicated by an independent Event
  • FIGS. 17A-B Relationship between Plasma and Urinary Endothelin and eGFR.
  • FIG. 18 Effect of RTA dh404 on Lung Histology in Rat Model of Monocrotaline-
  • Induced Pulmonary Arterial Hypertension Mean lung histology scores after evaluation by a board-certified veterinary pathologist, based on an increasing severity scale from 0 to 5.
  • Histology scores were analyzed non-parametrically for statistical differences using a one-way
  • FIG. 19 Effect of RTA dh404 on mRNA Expression of Nrf2 Target Genes in Rat Lung. Data are normalized to the housekeeping gene Rpll9 and presented as mean fold the vehicle control ⁇ S.E.M. *p ⁇ 0.05, **p ⁇ 0.01, and ***p ⁇ 0.001 vs. vehicle control.
  • FIG. 20 Effect of RTA dh404 on mRNA Expression of NF- ⁇ Target Genes in Rat
  • the present invention provides new methods for the treating and/or preventing endothelial dysfunction and/or pulmonary arterial hypertension in patients who are diagnosed with or at risk for cardiovascular disease (including patients diagnosed with or at risk for pulmonary arterial hypertension, other forms of pulmonary hypertension, atherosclerosis, restenosis, hyperlipidemia, hypercholesterolemia, metabolic syndrome, or obesity) and other diseases or conditions using bardoxolone methyl and analogs thereof.
  • BNP B-type natriuretic peptide
  • ACR albumin-to-creatinine ratio
  • the present invention concerns new methods of treating disorders that include endothelial dysfunction as a significant contributing factor. It also concerns the preparation of pharmaceutical compositions for the treatment of such disorders.
  • patients for treatment are selected on the basis of several criteria: (1) diagnosis of a disorder that involves endothelial dysfunction as a significant contributing factor; (2) lack of elevated levels of B-type natriuretic peptide (BNP; e.g., BNP titers must be ⁇ 200 pg/mL); (3) lack of chronic kidney disease (e.g., eGFR > 60) or lack of advanced chronic kidney disease (e.g., eGFR > 45); (4) lack of a history of left-sided myocardial disease; and (5) lack of a high ACR (e.g., ACR must be ⁇ 300 mg/g).
  • BNP B-type natriuretic peptide
  • patients with a diagnosis of type 2 diabetes are excluded.
  • patients with a diagnosis of cancer are excluded.
  • patients of advanced age e.g., >75 years
  • patients are closely monitored for rapid weight gain suggestive of fluid overload. For example, patients may be instructed to weigh themselves daily for the first four weeks of treatment and contact the prescribing physician if increases of greater than five pounds are observed.
  • Non-dialysis-dependent CKD-related pulmonary hypertension falls under WHO Class II and dialysis-dependent CKD-related pulmonary hypertension falls under WHO Class V (Bolignano et ah, 2013). Only a small percentage of stage 4-5 CKD patients present with WHO Class I pulmonary hypertension (i.e. pulmonary arterial hypertension), and, of note, these patients will be excluded according to the criteria above.
  • Kidney Disease and Type 2 Diabetes The Occurrence of Renal Events" (BEACON) was a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multinational, multicenter study designed to compare the efficacy and safety of bardoxolone methyl (BARD) to placebo (PBO) in patients with stage 4 chronic kidney disease and type 2 diabetes. A total of 2,185 patients were randomized 1 : 1 to once-daily administration of bardoxolone methyl (20 mg) or placebo.
  • the primary efficacy endpoint of the study was the time-to-first event in the composite endpoint defined as end-stage renal disease (ESRD; need for chronic dialysis, renal transplantation, or renal death) or cardiovascular (CV) death.
  • ESRD end-stage renal disease
  • CV cardiovascular
  • eGFR estimated glomerular filtration rate
  • time-to-first hospitalization for heart failure or death due to heart failure due to heart failure
  • time-to-first event of the composite endpoint consisting of non- fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure, or cardiovascular death.
  • An independent Events Adjudication Committee (EAC) blinded to study treatment assignment, evaluated whether renal events, cardiovascular events, and neurological events met the pre- specified definitions of the primary and secondary endpoints.
  • An IDMC consisting of external clinical experts supported by an independent statistical group, reviewed unblinded safety data throughout the study and made recommendations as appropriate.
  • Table 1 presents summary statistics on select demographic and baseline characteristics of patients enrolled in BEACON. Demographic characteristics were comparable across the two treatment groups. In all treatment groups combined, the average age was 68.5 years and 57% of the patients were male. The bardoxolone methyl arm had slightly more patients in the age subgroup >75 years than the placebo arm (27% in bardoxolone methyl arm versus 24% in the placebo arm). Mean weight and BMI across both treatment groups was 95.2 kg and 33.8 kg/m 2 , respectively.
  • Baseline kidney function was generally similar in the two treatment groups; mean baseline eGFR, as measured by the 4- variable Modified Diet in Renal Disease (MDRD) equation, was 22.5 mL/min/1.73 m 2 and the geometric mean albumin/creatinine ratio (ACR) was 215.5 mg/g for the combined treatment groups.
  • MDRD 4- variable Modified Diet in Renal Disease
  • Table includes only serious adverse events with onset more than 30 days after a patient's last dose of study drug.
  • Column header counts and denominators are the number of patients in the safety population. Each patient is counted at most once in each System Organ Class and Preferred Term.
  • Table 4 present a post-hoc analysis of demographic and select laboratory parameters of BEACON patients stratified by treatment group and occurrence of an adjudicated heart failure event.
  • the number of patients with heart failure includes all events through last date of contact (ITT Population).
  • BNP increases at Week 24 did not appear to be related to baseline BNP, baseline eGFR, changes in eGFR, or changes in ACR.
  • baseline ACR was significantly correlated with Week 24 changes from baseline in BNP, suggesting that the propensity for fluid retention may be associated with baseline severity of renal dysfunction, as defined by albuminuria status, and not with the general changes in renal function, as assessed by eGFR (Table 6).
  • Urinary sodium excretion data from BEACON sub-study patients revealed a clinically meaningful reduction in urine volume and excretion of sodium at Week 4 relative to baseline in the bardoxolone methyl-treated patients (Table 8). These decreases were significantly different from Week 4 changes in urine volume and urinary sodium observed in placebo- treated patients. Also of note, reductions in serum magnesium were not associated with renal loss of magnesium.
  • Urine Volume Urinary Sodium Urinary Potassium Urinary Magnesium (mL) (mmol/24 h) (mmol/24 h) (mmol/24 h)
  • Data include only BEACON patients enrolled in the 24-hour ABPM sub-study. Changes at Week 4 only calculated for patients with baseline and Week 4 data. * p ⁇ 0.05 for Week 4 versus baseline values within each treatment group; ⁇ p ⁇ 0.05 for Week 4 changes in BARD versus PBO patients.
  • Data are means. Data include patients with baseline and Week 8 data.
  • the first scheduled post-baseline assessment in BEACON was at Week 4. Since many of the heart failure events occurred prior to Week 4, the clinical database provides limited information to characterize these patients. Post-hoc review of the EAC case packets for heart failure cases that occurred prior to Week 4 was performed to assess clinical, vitals, laboratory, and imaging data collected at the time of the first heart failure event (Tables 10 and 1 1).
  • Bardoxolone methyl has also been tested in non-CKD disease settings.
  • RTA 402-C-0501 In early clinical studies of bardoxolone methyl in oncology patients (RTA 402-C-0501, RTA 402-C- 0702), after 21 consecutive days of treatment at doses that ranged from 5 to 1300 mg/day (crystalline formulation), no mean change in blood pressure was observed across all treatment groups.
  • RTA 402-C-0701 14 consecutive days of bardoxolone methyl treatment at doses of 5 and 25 mg/day (crystalline formulation) resulted in mean decreases in systolic and diastolic blood pressure (Table 13).
  • the urinary electrolyte, BNP, and blood pressure data collectively support that bardoxolone methyl treatment can differentially affect volume status, having no clinically detectable effect in healthy volunteers or early-stage CKD patients, while likely promoting fluid retention in patients with more advanced renal dysfunction and with traditional risk factors associated with heart failure at baseline.
  • the increases in eGFR are likely due to glomerular effects whereas effects on sodium and water regulation are tubular in origin.
  • eGFR change was not correlated with heart failure, the data suggest that effects on eGFR and sodium and water regulation are anatomically and pharmacologically distinct.
  • Event totals include only SAEs with onset no more than 30 days after a patient's last dose of study drug.
  • Avosentan was studied in stage 3-4 CKD patients with diabetic nephropathy in the ASCEND study, a large outcomes study to assess the time to first doubling of serum creatinine, ESRD, or death (Mann et ah, 2010). While the baseline eGFR in this study was slightly above the mean baseline eGFR in BEACON, patients in the ASCEND study had a mean ACR that was approximately seven-fold higher than BEACON (Table 18). Therefore, the overall cardiovascular risk profile was likely similar between the two studies.
  • ERA endothelin receptor antagonist
  • avosentan 25 or 50 mg or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade (ASCEND).
  • ASCEND angiotensin receptor blockade
  • ESRD was defined as need for dialysis or renal transplantation or an eGFR ⁇ 15 mL/min/1.73 m 2 .
  • Percentages for BEACON include all CHF and ESRD events through last date of contact and total number of deaths at the time of database lock (March 21, 2013).
  • ESRD in BEACON was defined as need for chronic dialysis, renal transplantation, or renal death; additional details and definitions for heart failure are outlined in the BEACON EAC Charter. * p ⁇ 0.05 vs. placebo.
  • endothelin-1 endothelin-1
  • ETA endothelin receptor type A
  • ETB endothelin receptor type B
  • ETB epithelial sodium channel
  • bardoxolone methyl reduces ET-1 expression in human cell lines, including mesangial cells found in the kidney as well as endothelial cell. Furthermore, in vitro and in vivo data suggest that bardoxolone methyl and analogs modulate the endothelin pathway to promote a vasodilatory phenotype by suppressing the vasoconstrictive ET A receptor and restoring normal levels of the vasodilatory ETB receptor. Thus, the potent activation of Nrf2 -related genes with bardoxolone methyl is associated with suppression of pathological endothelin signaling and facilitates vasodilation by modulating expression of ET receptors.
  • Data includes only ECG assessments collected on or before a patient's last dose of study drug. Visits are derived relative to a patient's first dose of study drug.
  • compromised renal function may be an important factor that contributes to a patient's inability to compensate for short-term fluid overload, and because relatively limited numbers of patients with earlier stages of CKD have been treated to date, exclusion of patients with CKD (e.g., patients with an eGFR ⁇ 60) from treatment with BARD and other AIMs may be prudent and is an element of the present invention.
  • pulmonary artery pressure in a patient in need thereof comprising administering to the patient bardoxolone methyl or an analog thereof in an amount sufficient to reduce the patient's pulmonary artery pressure.
  • Analogs of bardoxolone methyl include compounds of the formula:
  • Ri is -CN, halo, -CF 3 , or -C(0)R a , wherein R a is -OH, alkoxy (C i-4), "NH 2 , alkylaminO(ci-4), or -NH-S(0)2-alkyl( C i-4);
  • R2 is hydrogen or methyl; and R4 are each independently hydrogen, hydroxy, methyl or as defined below when either of these groups is taken together with group R ⁇ and is:
  • heteroaryl(c ⁇ 8) alkoxy(c ⁇ 8), alkenyloxy(c ⁇ 8), aryloxy(c ⁇ 8), aralk- oxy (c ⁇ 8), heteroaryloxy (c ⁇ 8), acyloxy (c ⁇ 8), alkylaminO(c ⁇ 8), dialkylaminO(c ⁇ 8), alkenylaminO(c ⁇ 8), arylaminO(c ⁇ 8), aralkylaminO(c ⁇ 8), heteroarylaminO(c ⁇ 8), alkylsulfonylamino(c ⁇ 8), amido(c ⁇ 8), -OC(0)NH-alkyl(c ⁇ 8), -OC(0)CH 2 NHC(0)0-?-butyl, -OCH 2 -alkylthio(c ⁇ 8), or a substituted version of any of these groups;
  • R c and R3, taken together, are -O- or -NRa- wherein Ra is hydrogen or alkyl( C ⁇ 4); or
  • R c and R4 taken together, are -O- or -NRa-, wherein Ra is hydrogen or alkyl(c ⁇ 4); or
  • alkyl(c ⁇ 8) alkenyl (c ⁇ 8), alkynyl (c ⁇ 8), aryl (c ⁇ 8), aralkyl (c ⁇ 8), hetero- aryl(c ⁇ 8), heterocycloalkyl (c ⁇ 8), alkoxy (c ⁇ 8), aryloxy (c ⁇ 8), aralkoxy(c ⁇ 8), heteroaryloxy(c ⁇ 8), acyloxy(c ⁇ 8), alkyl- amino(c ⁇ 8), dialkylamino(c ⁇ 8), arylamino(c ⁇ 8), or a substituted version of any of these groups;
  • Nrf2 antioxidant inflammation modulators. These compounds have shown the ability to activate Nrf2, as measured by elevated expression of one or more Nrf2 target genes (e.g., NQOl or HO-1 ; Dinkova-Kostova et al, 2005). Further, these compounds are capable of indirect and direct inhibition of pro-inflammatory transcription factors including NF -kappa B and STAT3 (Ahmad et al, 2006; Ahmad et al, 2008).
  • methods of preventing pulmonary arterial hypertension in a subject in need thereof comprising administering to the subject bardoxolone methyl or an analog thereof in an amount sufficient to prevent pulmonary arterial hypertension in the subject.
  • methods of preventing progression of pulmonary arterial hypertension in a subject in need thereof comprising administering to the subject bardoxolone methyl or an analog thereof in an amount sufficient to prevent progression of pulmonary arterial hypertension in the subject.
  • Triterpenoids biosynthesized in plants by the cyclization of squalene, are used for medicinal purposes in many Asian countries; and some, such as ursolic and oleanolic acid, are known to be anti-inflammatory and anti-carcinogenic (Huang et al, 1994; Nishino et al, 1988). However, the biological activity of these naturally-occurring molecules is relatively weak, and therefore the synthesis of new analogs to enhance their potency was undertaken (Honda et al, 1997; Honda et al, 1998).
  • oleanolic acid methyl-2-cyano-3,12-dioxooleana-l,9-dien-28-oic acid (CDDO-Me; RTA 402; bardoxolone methyl).
  • RTA 402 an antioxidant inflammation modulator (AIM)
  • AIM antioxidant inflammation modulator
  • RTA 402 has also been reported to activate the Keapl/Nrf2/ARE signaling pathway resulting in the production of several anti-inflammatory and antioxidant proteins, such as heme oxygenase-1 (HO-1). It induces the cytoprotective transcription factor Nrf2 and suppresses the activities of the pro-oxidant and pro-inflammatory transcription factors NF-KB and STAT3.
  • RTA 402 has demonstrated significant single agent anti-inflammatory activity in several animal models of inflammation such as renal damage in the cisplatin model and acute renal injury in the ischemia-reperfusion model.
  • significant reductions in serum creatinine have been observed in patients treated with RTA 402.
  • treatment may comprise administering to a subject a therapeutically effective amount of a compound of this invention, such as those described above or throughout this specification.
  • Treatment may be administered preventively in advance of a predictable state of oxidative stress (e.g., organ transplantation or the administration of therapy to a cancer patient), or it may be administered therapeutically in settings involving established oxidative stress and inflammation.
  • triterpenoids that may be used in accordance with the methods of this invention are shown here.
  • NQOl CD represents the concentration required to induce a two-fold increase in the expression of NQOl, an Nrf2 -regulated antioxidant enzyme, in Hepalclc7 murine hepatoma cells (Dinkova-Kostova et ah, 2005). All these results are orders of magnitude more active than, for example, the parent oleanolic acid molecule. In part because induction of antioxidant pathways resulting from Nrf2 activation provides important protective effects against oxidative stress and inflammation, analogs of RTA 402 may therefore also be used to for the treatment and/or prevention of diseases, such as pulmonary arterial hypertension.
  • the potency of the compounds of the present invention is largely derived from the addition of ⁇ , ⁇ -unsaturated carbonyl groups.
  • most activity of the compounds can be abrogated by the introduction of dithiothreitol (DTT), N-acetyl cysteine (NAC), or glutathione (GSH); thiol containing moieties that interact with ⁇ , ⁇ -unsaturated carbonyl groups (Wang et ah, 2000; Ikeda et ah, 2003; 2004; Shishodia et ah, 2006).
  • Biochemical assays have established that RTA 402 directly interacts with a critical cysteine residue (CI 79) on ⁇ (see below) and inhibits its activity (Shishodia et ah, 2006; Ahmad et ah, 2006).
  • ⁇ controls activation of NF-KB through the "classical" pathway which involves phosphorylation-induced degradation of IKB resulting in release of NF- ⁇ dimers to the nucleus.
  • this pathway is responsible for the production of many pro-inflammatory molecules in response to TNFa and other pro-inflammatory stimuli.
  • RTA 402 also inhibits the JAK/STAT signaling pathway at multiple levels. JAK proteins are recruited to transmembrane receptors (e.g., IL-6R) upon activation by ligands such as interferons and interleukins. JAKs then phosphorylate the intracellular portion of the receptor causing recruitment of STAT transcription factors. The STATs are then phosphorylated by JAKs, form dimers, and translocate to the nucleus where they activate transcription of several genes involved in inflammation. RTA 402 inhibits constitutive and IL-6-induced STAT3 phosphorylation and dimer formation and directly binds to cysteine residues in STAT3 (C259) and in the kinase domain of JAK1 (C1077).
  • JAK proteins are recruited to transmembrane receptors (e.g., IL-6R) upon activation by ligands such as interferons and interleukins. JAKs then phosphorylate the intracellular portion of the receptor causing recruitment of
  • Keapl is an actin-tethered protein that keeps the transcription factor Nrf2 sequestered in the cytoplasm under normal conditions (Kobayashi and Yamamoto, 2005). Oxidative stress results in oxidation of the regulatory cysteine residues on Keapl and causes the release of Nrf2. Nrf2 then translocates to the nucleus and binds to antioxidant response elements (AREs) resulting in transcriptional activation of many antioxidant and anti-inflammatory genes.
  • AREs antioxidant response elements
  • Another target of the Keapl /Nrf2/ARE pathway is heme oxygenase 1 (HO-1).
  • HO-1 breaks down heme into bilirubin and carbon monoxide and plays many antioxidant and anti-inflammatory roles (Maines and Gibbs, 2005).
  • HO-1 has recently been shown to be potently induced by the triterpenoids (Liby et al, 2005), including RTA 402.
  • RTA 402 and many structural analogs have also been shown to be potent inducers of the expression of other Phase 2 proteins (Yates et al., 2007).
  • RTA 402 is a potent inhibitor of NF-KB activation.
  • RTA 402 activates the Keapl /Nrf2/ARE pathway and induces expression of HO-1.
  • Compounds employed in methods of the invention may contain one or more asymmetrically-substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic, epimeric, and geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained.
  • the chiral centers of the compounds of the present invention can have the S or the R configuration.
  • Form B displays a bioavailability that is surprisingly better than that of Form A. Specifically the bioavailability of Form B was higher than that of Form A CDDO-Me in monkeys when the monkeys received equivalent dosages of the two forms orally, in gelatin capsules. See U.S. Patent Application Publication 2009/0048204, which is incorporated by reference herein in its entirety.
  • Form A can also be characterized by X-ray powder diffraction (XRPD) pattern (CuKa) comprising significant diffraction peaks at about 8.8, 12.9, 13.4, 14.2 and 17.4 ° ⁇ .
  • the X-ray powder diffraction of Form A is substantially as shown in FIG. 1A or FIG. IB.
  • Form B of CDDO-Me is in a single phase but lacks such a defined crystal structure.
  • Samples of Form B show no long-range molecular correlation, i.e., above roughly 20 A.
  • thermal analysis of Form B samples reveals a glass transition temperature (T g ) in a range from about 120°C to about 130°C.
  • T g glass transition temperature
  • T m melting temperature
  • Form B is typified by an XRPD spectrum (FIG. 1C) differing from that of Form A (FIG. 1A or FIG. IB).
  • Form B Since it does not have a defined crystal structure, Form B likewise lacks distinct XRPD peaks, such as those that typify Form A, and instead is characterized by a general "halo" XRPD pattern.
  • the non-crystalline Form B falls into the category of "X-ray amorphous" solids because its XRPD pattern exhibits three or fewer primary diffraction halos. Within this category, Form B is a "glassy" material.
  • Form A and Form B of CDDO-Me are readily prepared from a variety of solutions of the compound.
  • Form B can be prepared by fast evaporation or slow evaporation in MTBE, THF, toluene, or ethyl acetate.
  • Form A can be prepared in several ways, including via fast evaporation, slow evaporation, or slow cooling of a CDDO-Me solution in ethanol or methanol.
  • Preparations of CDDO-Me in acetone can produce either Form A, using fast evaporation, or Form B, using slow evaporation.
  • Non-limiting specific formulations of the compounds disclosed herein include CDDO-Me polymer dispersions. See, for example, PCT Publication WO 2010/093944, which is incorporated herein by reference in its entirety. Some of the formulations reported therein exhibit higher bioavailability than either the micronized Form A or nanocrystalline Form A formulations. Additionally, the polymer dispersion based formulations demonstrate further surprising improvements in oral bioavailability relative to the micronized Form B formulations. For example, the methacrylic acid copolymer, Type C and HPMC-P formulations showed the greatest bioavailability in the subject monkeys.
  • prodrugs employed in methods of the invention may also exist in prodrug form. Since prodrugs enhance numerous desirable qualities of pharmaceuticals, e.g., solubility, bioavailability, manufacturing, etc., the compounds employed in some methods of the invention may, if desired, be delivered in prodrug form. Thus, the invention contemplates prodrugs of compounds of the present invention as well as methods of delivering prodrugs. Prodrugs of the compounds employed in the invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.
  • any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable.
  • Examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.
  • Compounds employed in methods of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over compounds known in the prior art for use in the indications stated herein.
  • PAH is a substantially different disease than systemic hypertension.
  • PAH is characterized by high pulmonary artery and right ventricular pressures due to increased pulmonary vascular resistance; systemic hypertension is characterized by elevated pressure in the systemic circulation. Typically patients with PAH do not have systemic hypertension.
  • a drug may be effective as a treatment for systemic hypertension does not mean that it will also be effective for treating PAH.
  • a vasodilator drug that is effective for treating systemic hypertension such as the ACE-inhibitor Captopril
  • ACE-inhibitor Captopril can worsen pulmonary arterial hypertension and RV failure in patients with PAH.
  • Evidence for the potential deleterious effects of drugs used to treat systemic hypertension on PAH are given by Packer (1985), which is hereby incorporated by reference.
  • the one known exception to this limitation is that approximately 15%-20% of patients with idiopathic PAH respond to calcium channel blockers, agents that also may be used to treat systemic hypertension.
  • the diagnostic evaluation of PAH includes a pulmonary artery catheterization and acute challenge with adenosine, prostacyclin, or inhaled nitric oxide. If the patient has a greater than 10 mm Hg reduction in the mean pulmonary artery pressure and the mean pulmonary artery pressure decreases to less than or equal to 40 mm Hg with one of these agents, then testing to determine if the patient will respond to a calcium channel blocker may be performed (Rich et ah, 1992; Badesch et ah, 2004).
  • Pulmonary arterial hypertension is a life-threatening disease characterized by a marked and sustained elevation of pulmonary artery pressure and an increase in pulmonary vascular resistance leading to right ventricular (RV) failure and death.
  • Current therapeutic approaches for the treatment of chronic pulmonary arterial hypertension mainly provide symptomatic relief, as well as some improvement of prognosis. Although postulated for all treatments, evidence for direct anti-proliferative effects of most approaches is missing. In addition, the use of most of the currently applied agents is hampered by either undesired side effects or inconvenient drug administration routes.
  • Pathological changes of hypertensive pulmonary arteries include endothelial injury, proliferation and hyper-contraction of vascular smooth muscle cells (SMCs).
  • SMCs vascular smooth muscle cells
  • PAH with no apparent cause is termed primary pulmonary hypertension ("PPH").
  • PPH primary pulmonary hypertension
  • various pathophysiological changes associated with this disorder including vasoconstriction, vascular remodeling (i.e. proliferation of both media and intima of the pulmonary resistance vessels), and in situ thrombosis have been characterized (e.g., DAlonzo et al, 1991; Palevsky et al, 1989; Rubin, 1997; Wagenvoort and Wagenvoort, 1970; Wood, 1958).
  • Impairment of vascular and endothelial homeostasis is evidenced from a reduced synthesis of prostacyclin (PGI 2 ), increased thromboxane production, decreased formation of nitric oxide and increased synthesis of endothelin- 1 (Giaid and Sal eh, 1995; Xue and Johns, 1995).
  • PPI 2 prostacyclin
  • the intracellular free calcium concentration of vascular smooth muscle cells of pulmonary arteries in PPH has been reported to be elevated.
  • Pulmonary arterial hypertension is defined as pulmonary vascular disease affecting the pulmonary arterioles resulting in an elevation in pulmonary artery pressure and pulmonary vascular resistance but with normal or only mildly elevated left-sided filling pressures (McLaughlin and Rich, 2004).
  • PAH is caused by a constellation of diseases that affect the pulmonary vasculature.
  • PAH can be caused by or associated with collagen vascular disorders, such as systemic sclerosis (scleroderma), uncorrected congenital heart disease, liver disease, portal hypertension, HIV infection, Hepatitis C, certain toxins, splenectomy, hereditary hemorrhagic telangiectasia, and primary genetic abnormalities.
  • a mutation in the bone morphogenetic protein type 2 receptor has been identified as a cause of familial primary pulmonary hypertension (PPH) (Lane et al, 2000; Deng et al, 2000). It is estimated that 6% of cases of PPH are familial, and that the rest are "sporadic.” The incidence of PPH is estimated to be approximately 1 case per 1 million population. Secondary causes of PAH have a much higher incidence.
  • the pathologic signature of PAH is the plexiform lesion of the lung, which consists of obliterative endothelial cell proliferation and vascular smooth muscle cell hypertrophy in small precapillary pulmonary arterioles. PAH is a progressive disease associated with a high mortality. Patients with PAH may develop right ventricular (RV) failure, the extent of which predicts outcome (McLaughlin et al, 2002).
  • RV right ventricular
  • the evaluation and diagnosis of PAH is reviewed by McLaughlin and Rich (2004) and McGoon et al. (2004).
  • a clinical history such as symptoms of shortness of breath, a family history of PAH, presence of risk factors, and findings on physical examination, chest X-ray and electrocardiogram may lead to the suspicion of PAH.
  • the next step in the evaluation will usually include an echocardiogram.
  • the echocardiogram can be used to estimate the pulmonary artery pressure from the Doppler analysis of the tricuspid regurgitation jet.
  • the echocardiogram can also be used to evaluate the function of the right and left ventricle, and the presence of valvular heart disease, such as mitral stenosis and aortic stenosis.
  • the echocardiogram can also be useful in diagnosing congenital heart disease, such as an uncorrected atrial septal defect or patent ductus arteriosus. Findings on echocardiogram consistent with a diagnosis of PAH would include: 1) Doppler evidence for elevated pulmonary artery pressure; 2) right atrial enlargement; 3) right ventricular enlargement and/or hypertrophy; 4) absence of mitral stenosis, pulmonic stenosis, and aortic stenosis; 5) normal size or small left ventricle; 6) relative preservation of or normal left ventricular function. To confirm the diagnosis of PAH a cardiac catheterization to directly measure the pressures in the right side of the heart and in the pulmonary vasculature is mandatory.
  • PCWP pulmonary capillary wedge pressure
  • a commonly used definition of mean pulmonary artery pressure is one-third the value of the systolic pulmonary artery pressure plus two-thirds of the diastolic pulmonary artery pressure.
  • Severe PAH may be defined as a mean pulmonary artery pressure greater than or equal to 25 mm Hg with a PCWP less than or equal to 15-16 mm Hg, and a pulmonary vascular resistance (PVR) greater than or equal to 240 dynes sec/cm 5 .
  • Pulmonary vascular resistance is defined as the mean pulmonary artery pressure minus the PCWP divided by the cardiac output. This ratio is multiplied by 80 to express the result in dyne sec/cm 5 .
  • the PVR may also be expressed in millimeters Hg per liter per minute, which is referred to as Wood Units.
  • the PVR in a normal adult is 67 ⁇ 23 dyne sec/cm 5 or 1 Wood Unit (McLaughlin and Rich, 2004; McGoon et al, 2004; Galie et al, 2005).
  • Wood Units millimeters Hg per liter per minute
  • the PVR in a normal adult is 67 ⁇ 23 dyne sec/cm 5 or 1 Wood Unit (McLaughlin and Rich, 2004; McGoon et al, 2004; Galie et al, 2005).
  • patients with left sided myocardial disease or valvular heart disease are typically excluded (Galie et al, 2005).
  • the status of pulmonary arterial hypertension can be assessed in patients according to the World Health Organization (WHO) classification (modified after the New York Association Functional Classification) as detailed below:
  • WHO World Health Organization
  • Class I Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope.
  • Class II Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dispend or fatigue, chest pain or near syncope.
  • Class III Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope.
  • Class rv Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure.
  • Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.
  • PDE-V phosphodiesterase type V
  • sildenafil and tadalafil have been approved for the treatment of PAH (Lee et al, 2005; Kataoka et al, 2005).
  • PDE-V inhibition results in an increase in cyclic GMP, which leads to vasodilation of the pulmonary vasculature.
  • Treprostinil an analogue of PGL, can be administered subcutaneously to appropriately selected patients with PAH (Oudiz et al, 2004; Vachiery and Naeije, 2004).
  • Iloprost another prostacyclin analogue, can be administered in nebulized form by direct inhalation (Galie et ah, 2002).
  • Riociguat a stimulator of soluble guanylate cyclas (sGC), is also approved for the treatment of PAH.
  • PAH primary pulmonary hypertension or PPH
  • idiopathic PAH a stimulator of soluble guanylate cyclas
  • scleroderma a stimulator of soluble guanylate cyclas
  • mixed connective tissue disease a systemic lupus erythematosus
  • HIV infection toxins, such as phentermine/fenfluramine, congenital heart disease, Hepatitis C, liver cirrhosis, chronic thrombo-embolic pulmonary artery hypertension (distal or inoperable), hereditary hemorrhagic telangiectasia, and splenectomy.
  • CV disease cardiovascular disease
  • the compounds and methods of this invention may be used for treating patients with cardiovascular disease. See U.S. Patent Application 12/352,473, which is incorporated by reference herein in its entirety.
  • Cardiovascular (CV) disease is among the most important causes of mortality worldwide, and is the leading cause of death in many developed countries.
  • the etiology of CV disease is complex, but the majority of causes are related to inadequate or completely disrupted supply of blood to a critical organ or tissue. Frequently such a condition arises from the rupture of one or more atherosclerotic plaques, which leads to the formation of a thrombus that blocks blood flow in a critical vessel.
  • Such thrombosis is the principal cause of heart attacks, in which one or more of the coronary arteries is blocked and blood flow to the heart itself is disrupted.
  • ischemia- reperfusion injury a phenomenon known as ischemia- reperfusion injury.
  • Similar damage occurs in the brain during a thrombotic stroke, when a cerebral artery or other major vessel is blocked by thrombosis.
  • Hemorrhagic strokes in contrast, involve rupture of a blood vessel and bleeding into the surrounding brain tissue. This creates oxidative stress in the immediate area of the hemorrhage, due to the presence of large amounts of free heme and other reactive species, and ischemia in other parts of the brain due to compromised blood flow.
  • Subarachnoid hemorrhage which is frequently accompanied by cerebral vasospasm, also causes ischemia/reperfusion injury in the brain.
  • Atherosclerosis may be so extensive in critical blood vessels that stenosis (narrowing of the arteries) develops and blood flow to critical organs (including the heart) is chronically insufficient.
  • stenosis narrowing of the arteries
  • critical organs including the heart
  • chronic ischemia can lead to end-organ damage of many kinds, including the cardiac hypertrophy associated with congestive heart failure.
  • Atherosclerosis the underlying defect leading to many forms of cardiovascular disease, occurs when a physical defect or injury to the lining (endothelium) of an artery triggers an inflammatory response involving the proliferation of vascular smooth muscle cells and the infiltration of leukocytes into the affected area.
  • a complicated lesion known as an atherosclerotic plaque may form, composed of the above-mentioned cells combined with deposits of cholesterol-bearing lipoproteins and other materials (e.g., Hansson et al, 2006).
  • RTA dh404 lessened diabetes-associated atherosclerosis.
  • an animal model was used in conjunction with RTA dh404 as a surrogate for RTA 402.
  • treatment with RTA dh404 in an inverse dose-dependent manner, was found to reduce plaque in the arch, thoracic, and abdominal regions of the aorta as well as attenuate lesion deposition within the aortic sinus (Tarn et al, 2014, incorporated herein by reference in its entirety).
  • cardiovascular disease treatments for cardiovascular disease include preventive treatments, such as the use of drugs intended to lower blood pressure or circulating levels of cholesterol and lipoproteins, as well as treatments designed to reduce the adherent tendencies of platelets and other blood cells (thereby reducing the rate of plaque progression and the risk of thrombus formation). More recently, drugs such as streptokinase and tissue plasminogen activator have been introduced and are used to dissolve the thrombus and restore blood flow.
  • Surgical treatments include coronary artery bypass grafting to create an alternative blood supply, balloon angioplasty to compress plaque tissue and increase the diameter of the arterial lumen, and carotid endarterectomy to remove plaque tissue in the carotid artery.
  • Such treatments may be accompanied by the use of stents, expandable mesh tubes designed to support the artery walls in the affected area and keep the vessel open.
  • drug-eluting stents has become common in order to prevent post-surgical restenosis (renarrowing of the artery) in the affected area.
  • These devices are wire stents coated with a biocompatible polymer matrix containing a drug that inhibits cell proliferation (e.g., paclitaxel or rapamycin). The polymer allows a slow, localized release of the drug in the affected area with minimal exposure of non-target tissues.
  • HO-1 cardiovascular disease
  • cardiovascular disorders including but not limited to atherosclerosis, hypertension, myocardial infarction, chronic heart failure, stroke, subarachnoid hemorrhage, and restenosis.
  • Administration of the compounds of the present invention to a patient will follow general protocols for the administration of pharmaceuticals, taking into account the toxicity, if any, of the drug. It is expected that the treatment cycles would be repeated as necessary.
  • the compounds of the present invention may be administered by a variety of methods, e.g., orally or by injection (e.g. subcutaneous, intravenous, intraperitoneal, etc.).
  • the active compounds may be coated by a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound. They may also be administered by continuous perfusion/infusion of a disease or wound site.
  • Specific examples of formulations, including a polymer-based dispersion of CDDO-Me that showed improved oral bioavailability, are provided in U.S. Application No. 12/191, 176, which is incorporated herein by reference in its entirety.
  • the therapeutic compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent.
  • suitable diluents include saline and aqueous buffer solutions.
  • Liposomes include water-in- oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al, 1984).
  • the therapeutic compound may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally.
  • Dispersions may be prepared in, e.g., glycerol, liquid polyethylene glycols, mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the therapeutic compound into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the therapeutic compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the therapeutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • the therapeutic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount of the therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient.
  • the therapeutic compound may also be administered topically to the skin, eye, or mucosa. Alternatively, if local delivery to the lungs is desired the therapeutic compound may be administered by inhalation in a dry-powder or aerosol formulation.
  • the therapeutic compound may be formulated in a biocompatible matrix for use in a drug-eluting stent.
  • the actual dosage amount of a compound of the present invention or composition comprising a compound of the present invention administered to a subject may be determined by physical and physiological factors such as age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the subject and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. The dosage may be adjusted by the individual physician in the event of any complication.
  • the pharmaceutically effective amount is a daily dose from about 0.1 mg to about 500 mg of the compound. In some variations, the daily dose is from about 1 mg to about 300 mg of the compound. In some variations, the daily dose is from about 10 mg to about 200 mg of the compound. In some variations, the daily dose is about 25 mg of the compound. In other variations, the daily dose is about 75 mg of the compound. In still other variations, the daily dose is about 150 mg of the compound. In further variations, the daily dose is from about 0.1 mg to about 30 mg of the compound. In some variations, the daily dose is from about 0.5 mg to about 20 mg of the compound. In some variations, the daily dose is from about 1 mg to about 15 mg of the compound. In some variations, the daily dose is from about 1 mg to about 10 mg of the compound. In some variations, the daily dose is from about 1 mg to about 5 mg of the compound.
  • the pharmaceutically effective amount is a daily dose is 0.01 - 25 mg of compound per kg of body weight. In some variations, the daily dose is 0.05 - 20 mg of compound per kg of body weight. In some variations, the daily dose is 0.1 - 10 mg of compound per kg of body weight. In some variations, the daily dose is 0.1 - 5 mg of compound per kg of body weight. In some variations, the daily dose is 0.1 - 2.5 mg of compound per kg of body weight.
  • the pharmaceutically effective amount is a daily dose is of 0.1 - 1000 mg of compound per kg of body weight. In some variations, the daily dose is 0.15 - 20 mg of compound per kg of body weight. In some variations, the daily dose is 0.20 - 10 mg of compound per kg of body weight. In some variations, the daily dose is 0.40 - 3 mg of compound per kg of body weight. In some variations, the daily dose is 0.50 - 9 mg of compound per kg of body weight. In some variations, the daily dose is 0.60 - 8 mg of compound per kg of body weight. In some variations, the daily dose is 0.70 - 7 mg of compound per kg of body weight. In some variations, the daily dose is 0.80 - 6 mg of compound per kg of body weight. In some variations, the daily dose is 0.90 - 5 mg of compound per kg of body weight. In some variations, the daily dose is from about 1 mg to about 5 mg of compound per kg of body weight.
  • An effective amount typically will vary from about 0.001 mg/kg to about 1,000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 0.2 mg/kg to about 250 mg/kg, from about 0.3 mg/kg to about 150 mg/kg, from about 0.3 mg/kg to about 100 mg/kg, from about 0.4 mg/kg to about 75 mg/kg, from about 0.5 mg/kg to about 50 mg/kg, from about 0.6 mg/kg to about 30 mg/kg, from about 0.7 mg/kg to about 25 mg/kg, from about 0.8 mg/kg to about 15 mg/kg, from about 0.9 mg/kg to about 10 mg/kg, from about 1 mg/kg to about 5 mg/kg, from about 100 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, or from about 10.0 mg/kg to about 150 mg/kg, in one or more dose administrations daily, for one or several days (depending, of course, of the
  • suitable dose ranges include 1 mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and 500 mg to 1,000 mg per day. In some particular embodiments, the amount is less than 10,000 mg per day with a range, for example, of 750 mg to 9,000 mg per day.
  • the effective amount may be less than 1 mg/kg/day, less than 500 mg/kg/day, less than 250 mg/kg/day, less than 100 mg/kg/day, less than 50 mg/kg/day, less than 25 mg/kg/day, less than 10 mg/kg/day, or less than 5 mg/kg/day. It may alternatively be in the range of 1 mg/kg/day to 200 mg/kg/day.
  • the unit dosage may be an amount that reduces blood glucose by at least 40% as compared to an untreated subject.
  • the unit dosage is an amount that reduces blood glucose to a level that is within ⁇ 10% of the blood glucose level of a non- diabetic subject.
  • a dose may also comprise from about 1 microgram/kg/body weight, about 5 microgram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram kg/body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body weight, about 350 milligram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein.
  • a range of about 1 mg/kg/body weight to about 5 mg/kg/body weight, a range of about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 microgram/kg/body weight to about 500 milligram/kg/body weight, etc. can be administered, based on the numbers described above.
  • a pharmaceutical composition of the present invention may comprise, for example, at least about 0.1% of a compound of the present invention.
  • the compound of the present invention may comprise between about 2% to about 75% of the weight of the unit, or between about 25% to about 60%, for example, and any range derivable therein.
  • Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation.
  • subjects may be administered two doses daily at approximately 12 hour intervals.
  • the agent is administered once a day.
  • the agent(s) may be administered on a routine schedule.
  • a routine schedule refers to a predetermined designated period of time.
  • the routine schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined.
  • routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks therebetween.
  • predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc.
  • the invention provides that the agent(s) may taken orally and that the timing of which is or is not dependent upon food intake.
  • the agent can be taken every morning and/or every evening, regardless of when the subject has eaten or will eat.
  • Non-limiting specific formulations include CDDO-Me polymer dispersions (see U.S. Application No. 12/191, 176, filed August 13, 2008, which is incorporated herein by reference). Some of the formulations reported therein exhibited higher bioavailability than either the micronized Form A or nanocrystalline Form A formulations. Additionally, the polymer dispersion based formulations demonstrated further surprising improvements in oral bioavailability relative to the micronized Form B formulations. For example, the methacrylic acid copolymer, Type C and HPMC-P formulations showed the greatest bioavailability in the subject monkeys. VI. Combination Therapy
  • the compounds of the present invention may also find use in combination therapies.
  • Effective combination therapy may be achieved with a single composition or pharmacological formulation that includes both agents, or with two distinct compositions or formulations, administered at the same time, wherein one composition includes a compound of this invention, and the other includes the second agent(s).
  • the therapy may precede or follow the other agent treatment by intervals ranging from minutes to months.
  • COX inhibitors including arylcarboxylic acids (salicylic acid, acetyls alicy lie acid, diflunisal, choline magnesium trisalicylate, salicylate, benorylate, flufenamic acid, mefenamic acid, meclofenamic acid and triflumic acid), arylalkanoic acids (diclofenac, fenclofenac, alclofenac, fentiazac, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, fenbufen, suprofen, indoprofen, tiaprofenic acid, benoxaprofen, pirprofen, tolmetin, zomepirac, clopinac, indomethacin and sulindac
  • arylcarboxylic acids salicylic acid, acetyls alicy lie acid, diflun
  • FDA approved treatments for pulmonary hypertension include prostanoids (epoprostenol, iloprost, and treprostinil), endothelin receptor antagonists (bosentan, ambrisentan, and macitentan), phosphodiesterase-5 inhibitors (sildenafil and tadalafil), and sGC stimulators (riociguat).
  • prostanoids epoprostenol, iloprost, and treprostinil
  • endothelin receptor antagonists bosentan, ambrisentan, and macitentan
  • phosphodiesterase-5 inhibitors silicafil and tadalafil
  • sGC stimulators riociguat
  • rho-kinase inhibitors such as Y-27632, fasudil, and H-1152P
  • epoprostenol derivatives such as prostacyclin, treprostinil, beraprost, and iloprost
  • serotonin blockers such as sarpogrelate
  • endothelin receptor antagonists such as besentan, sitaxsentan, ambrisentan, and TBC3711
  • PDE inhibitors such as sildenafil, tadalafil, udenafil, and vardenafil
  • calcium channel blockers such as amlodipine, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, aranidipine, bamidipine, be
  • nitric oxide such as acetyl- L-carnitine, octacosanol, evening primrose oil, vitamin B6, tyrosine, phenylalanine, vitamin C, L-dopa, or a combination of several antioxidants may be used in conjunction with the compounds of the current invention.
  • NO nitric oxide
  • prostaglandins such as acetyl- L-carnitine, octacosanol, evening primrose oil, vitamin B6, tyrosine, phenylalanine, vitamin C, L-dopa, or a combination of several antioxidants may be used in conjunction with the compounds of the current invention.
  • Other particular secondary therapies include immunosuppressants (for transplants and autoimmune-related RKD), anti-hypertensive drugs (for high blood pressure-related RKD, e.g., angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), insulin (for diabetic RKD), lipid/cholesterol-lowering agents (e.g., HMG-CoA reductase inhibitors such as atorvastatin or simvastatin), treatments for hyperphosphatemia or hyperparathyroidism associated with CKD (e.g., sevelamer acetate, cinacalcet), dialysis, and dietary restrictions (e.g., protein, salt, fluid, potassium, phosphorus).
  • immunosuppressants for transplants and autoimmune-related RKD
  • anti-hypertensive drugs for high blood pressure-related RKD, e.g., angiotensin-converting enzyme inhibitors and angiotensin receptor blockers
  • insulin for diabetic RKD
  • BNP B-type natriuretic peptide
  • the functions of BNP include natriuresis, vasodilation, inhibition of the renin-angiotensin-aldosterone axis, and inhibition of sympathetic nerve activity.
  • the plasma concentration of BNP is elevated among patients with congestive heart failure (CHF), and increases in proportion to the degree of left ventricular dysfunction and the severity of CHF symptoms.
  • CHF congestive heart failure
  • B- type natriuretic peptide (BNP) levels may be determined by the following method(s): protein immunoassays as described in US Patent Publication 2011/0201130, which is incorporated by reference in its entirety herein.
  • BNP B- type natriuretic peptide
  • dipstick protein tests are quantified by measuring the total quantity of protein in a 24-hour urine collection test.
  • PCR protein/creatinine ratio
  • the UK Chronic Kidney Disease Guidelines (2005; which are incorporated herein by reference in their entirety) states PCR is a better test than 24-hour urinary protein measurement.
  • Proteinuria is defined as a protein/creatinine ratio greater than 45 mg/mmol (which is equivalent to albumin/creatinine ratio of greater than 30 mg/mmol or approximately 300 mg/g as defined by dipstick proteinuria of 3+) with very high levels of proteinuria being for a PCR greater than 100 mg/mmol.
  • Protein dipstick measurements should not be confused with the amount of protein detected on a test for microalbuminuria, which denotes values for protein for urine in mg/day versus urine protein dipstick values which denote values for protein in mg/dL. That is, there is a basal level of proteinuria that can occur below 30 mg/day which is considered non- pathological. Values between 30-300 mg/day are termed microalbuminuria which is considered pathologic. Urine protein lab values for microalbumin of >30 mg/day correspond to a detection level within the "trace" to " 1+" range of a urine dipstick protein assay. Therefore, positive indication of any protein detected on a urine dipstick assay obviates any need to perform a urine microalbumin test as the upper limit for microalbuminuria has already been exceeded.
  • This formula expects weight to be measured in kilograms and creatinine to be measured in mg/dL, as is standard in the USA. The resulting value is multiplied by a constant of 0.85 if the patient is female. This formula is useful because the calculations are simple and can often be performed without the aid of a calculator.
  • Constant is 1.23 for men and 1.04 for women.
  • the CG equation assumes that a woman will have a 15% lower creatinine clearance than a man at the same level of serum creatinine.
  • eGFR values may be calculated using the Modification of Diet in Renal Disease (MDRD) formula.
  • MDRD Diet in Renal Disease
  • eGFR 175 x Standardized serum creatinine -1 154 x Age ⁇ 0 - 203 x C where C is 1.212 if the patient is a black male, 0.899 if the patient is a black female, and 0.742 if the patient is a non-black female. Serum creatinine values are based on the IDMS- traceable creatinine determination (see below).
  • Chronic kidney disease is defined as a GFR less than 60 mL/min/1.73 m 2 that is present for three or more months.
  • PA pulmonary artery
  • TTE trans- thoracic echocardiogram
  • right heart catheterization There are two main methods used to measure pulmonary artery (PA) pressures: trans- thoracic echocardiogram (TTE) and right heart catheterization.
  • An echocardiogram is an ultrasound of the heart; trans-thoracic means that the ultrasound probe rests on the outside of the chest (or “thorax”). None is inserted into the body, so this test is called “non-invasive” and can be performed on an outpatient basis.
  • Both the right ventricle and the beginning of the pulmonary arteries can be seen on the TTE.
  • the TTE looks at the right ventricle as it pumps blood into the pulmonary arteries. Some of the blood from the right ventricle, instead of going forward into the pulmonary arteries, naturally leaks back into the right atrium via the tricuspid valve. When PA pressures are higher than they should be, it is harder for the right ventricle to pump blood forward and more of it therefore leaks back through the tricuspid valve.
  • the TTE can measure the amount of leakage (or regurgitation) and use that to estimate the PA pressure. In some patients, PAH is seen only with exercise. In these cases, a TTE can be done to measure PA pressure after an exercise test (such as walking on a treadmill).
  • a right heart catheterization is a more invasive test that requires the placement of a pressure monitor directly into the pulmonary arteries. This technique allows for direct measurement of the systolic and diastolic PA pressures, and thus often results in more accurate measurements.
  • a serum creatinine test measures the level of creatinine in the blood and provides an estimate glomerular filtration rate.
  • Serum creatinine values in the BEACON and BEAM trials were based on the isotope dilution mass spectrometry (IDMS)-traceable creatinine determinations.
  • IDMS isotope dilution mass spectrometry
  • Other commonly used creatinine assay methodologies include (1) alkaline picrate methods (e.g., Jaffe method [classic] and compensated [modified] Jaffe methods), (2) enzymatic methods, (3) high-performance liquid chromatography, (4) gas chromatography, and (5) liquid chromatography.
  • the IDMS method is widely considered to be the most accurate assay (Peake and Whiting, 2006, which is incorporated herein by reference in its entirety).
  • Cystatin C can be measured in a random sample of serum using immunoassays such as nephelometry or particle-enhanced turbidimetry. Reference values differ in many populations and with sex and age. Across different studies, the mean reference interval (as defined by the 5th and 95th percentile) was between 0.52 and 0.98 mg/L. For women, the average reference interval is 0.52 to 0.90 mg/L with a mean of 0.71 mg/L. For men, the average reference interval is 0.56 to 0.98 mg/L with a mean of 0.77 mg/L. The normal values decrease until the first year of life, remaining relatively stable before they increase again, especially beyond age 50. Creatinine levels increase until puberty and differ according to gender from then on, making their interpretation problematic for pediatric patients.
  • the reference interval (as defined by the 1st and 99th percentile) was between 0.57 and 1.12 mg/L. This interval was 0.55 - 1.18 for women and 0.60 - 1.11 for men. Non-Hispanic blacks and Mexican Americans had lower normal cystatin C levels. Other studies have found that in patients with an impaired renal function, women have lower and blacks have higher cystatin C levels for the same GFR. For example, the cutoff values of cystatin C for chronic kidney disease for a 60-year-old white women would be 1.12 mg/L and 1.27 mg/L in a black man (a 13% increase). For serum creatinine values adjusted with the MDRD equation, these values would be 0.95 mg/dL to 1.46 mg/dL (a 54% increase).
  • Serum levels of uric acid are typically determined by clinical chemistry methods, e.g., spectrophotometric measurement based on the reaction of uric acid with a specified reagent to form a colored reaction product. Because uric acid determination is a standard clinical chemistry test, a number of products are commercially available for this purpose.
  • blood test results should always be interpreted using the range provided by the laboratory that performed the test.
  • Uric acid concentrations in blood plasma above and below the normal range are known, respectively, as hyperuricemia and hypouricemia.
  • uric acid concentrations in urine above and below normal are known as hyperuricosuria and hypouricosuria.
  • CECs were isolated from whole blood by using CD 146 Ab (an antibody to the CD 146 antigen that is expressed on endothelial cells and leukocytes). After CEC isolation, a FITC (fluorescein isothiocyanate) conjugated CD 105 Ab (a specific antibody for endothelial cells) was used to identify CECs using the CellSearchTM system. A fluorescent conjugate of CD45 Ab was added to stain the leukocytes, and these were then gated out. For a general overview of this method, see Blann et al. (2005), which is incorporated herein by reference in its entirety. CEC samples were also assessed for the presence of iNOS by immunostaining. VIII. Definitions
  • the symbol “-” means a single bond
  • “ ⁇ ” means triple bond.
  • the symbol " " represents an optional bond, which if present is either single or double.
  • the covalent bond symbol when connecting one or two stereogenic atoms does not indicate any preferred stereochemistry. Instead, it cover all stereoisomers as well as mixtures thereof.
  • the symbol “ * ⁇ " when drawn perpendicularly across a bond (e. .,1- CH 3 for methyl) indicates a point of attachment of the group.
  • the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment.
  • the symbol “ ⁇ ⁇ " means a single bond where the group attached to the thick end of the wedge is "out of the page.”
  • the symbol “"”Ml " means a single bond where the group attached to the thick end of the wedge is “into the page”.
  • the symbol “ ⁇ . " means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended.
  • the bond orders described above are not limiting when one of the atoms connected by the bond is a metal atom (M).
  • R may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed.
  • R may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed.
  • R may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise.
  • Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals -CH-), so long as a stable structure is formed.
  • R may reside on either the 5-membered or the 6- membered ring of the fused ring system.
  • (Cn) defines the exact number (n) of carbon atoms in the group/class.
  • (C ⁇ n) defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number as small as possible for the group in question, e.g., it is understood that the minimum number of carbon atoms in the group “alkenyl(c ⁇ 8) " or the class “alkene(c ⁇ 8)” is two.
  • alkoxy(c ⁇ io) designates those alkoxy groups having from 1 to 10 carbon atoms.
  • (Cn-n') defines both the minimum (n) and maximum number ( ⁇ ') of carbon atoms in the group.
  • alkyl( C2 -io) designates those alkyl groups having from 2 to 10 carbon atoms.
  • saturated means the compound or group so modified has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below.
  • one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon- carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded.
  • aliphatic when used without the "substituted” modifier signifies that the compound/group so modified is an acyclic or cyclic, but non-aromatic hydrocarbon compound or group.
  • the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic).
  • Aliphatic compounds/groups can be saturated, that is joined by single bonds (alkanes/alkyl), or unsaturated, with one or more double bonds (alkenes/alkenyl) or with one or more triple bonds (alkynes/alkynyl).
  • alkyl when used without the "substituted” modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, and no atoms other than carbon and hydrogen.
  • cycloalkyl is a subset of alkyl, with the carbon atom that forms the point of attachment also being a member of one or more non-aromatic ring structures wherein the cycloalkyl group consists of no atoms other than carbon and hydrogen.
  • the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the ring or ring system.
  • the groups -CH 3 (Me), -CH 2 CH 3 (Et), -CH 2 CH 2 CH 3 (zi-Pr or propyl), -CH(CH 3 ) 2 ( ⁇ - ⁇ , ; Pr or isopropyl), -CH(CH 2 ) 2 (cyclopropyl), -CH 2 CH 2 CH 2 CH 3 (w-Bu), -CH(CH 3 )CH 2 CH 3 (sec-butyl), -CH 2 CH(CH 3 ) 2 (isobutyl), -C(CH 3 ) 3 (tert-butyl, /-butyl, /-Bu or 3 ⁇ 4u), -CH 2 C(CH 3 ) 3 (weo-pentyl), cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexylmethyl are non-limiting examples of alkyl groups.
  • alkanediyl when used without the “substituted” modifier refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen.
  • alkanediyl groups (methylene), -CH 2 CH 2 - -CH 2 C(CH 3 ) 2 CH 2 - -CH 2 CH 2 CH 2 - and , are non- limiting examples of alkanediyl groups.
  • alkane refers to the compound H-R, wherein R is alkyl as this term is defined above.
  • substituents one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -NO2, -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH3, -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , or -S(0) 2 NH 2 .
  • haloalkyl is a subset of substituted alkyl, in which one or more hydrogen atoms has been substituted with a halo group and no other atoms aside from carbon, hydrogen and halogen are present.
  • the group, -CH C1 is a non-limiting example of a haloalkyl.
  • fluoroalkyl is a subset of substituted alkyl, in which one or more hydrogen has been substituted with a fluoro group and no other atoms aside from carbon, hydrogen and fluorine are present.
  • the groups, -CH 2 F, -CF 3 , and -CH 2 CF 3 are non-limiting examples of fluoroalkyl groups.
  • alkenyl when used without the "substituted” modifier refers to an monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen.
  • alkenediyl when used without the "substituted” modifier refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen.
  • alkenediyl groups are non- limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming an aromatic structure.
  • alkene or "olefin” are synonymous and refer to a compound having the formula H-R, wherein R is alkenyl as this term is defined above.
  • a "terminal alkene” refers to an alkene having just one carbon-carbon double bond, wherein that bond forms a vinyl group at one end of the molecule.
  • alkynyl when used without the "substituted” modifier refers to an monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen.
  • alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds.
  • the groups, -C ⁇ CH, -C ⁇ CCH 3 , and -CH 2 C ⁇ CCH 3 are non-limiting examples of alkynyl groups.
  • An “alkyne” refers to the compound H-R, wherein R is alkynyl.
  • one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, - H 2 , -N0 2 , -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , or -S(0) 2 NH 2 .
  • aryl when used without the "substituted” modifier refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more six-membered aromatic ring structure, wherein the ring atoms are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present.
  • Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C 6 H 4 CH 2 CH 3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl.
  • the term "arenediyl” when used without the “substituted” modifier refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structure(s) wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen.
  • the term does not preclude the presence of one or more alkyl, aryl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting).
  • arenediyl groups include:
  • an “arene” refers to the compound H-R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes. When any of these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 3 ⁇ 4 -N0 2 , -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , or -S(0) 2 NH 2 .
  • aralkyl when used without the “substituted” modifier refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above.
  • Non-limiting examples of aralkyls are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.
  • aralkyl When the term aralkyl is used with the "substituted" modifier one or more hydrogen atom from the alkanediyl and/or the aryl group has been independently replaced by -OH, -F, -CI, -Br, -I, - H 2 , -N0 2 , -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , ⁇ NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , or -S(0) 2 NH 2 .
  • substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-l-yl.
  • heteroaryl when used without the "substituted” modifier refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl, aryl, and/or aralkyl groups (carbon number limitation permitting) attached to the aromatic ring or aromatic ring system.
  • heteroaryl groups include furanyl, imidazolyl, indolyl, indazolyl (Im), isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridinyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl.
  • N-heteroaryl refers to a heteroaryl group with a nitrogen atom as the point of attachment.
  • heteroaryl when used without the "substituted” modifier refers to an divalent aromatic group, with two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aromatic nitrogen atom as the two points of attachment, said atoms forming part of one or more aromatic ring structure(s) wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings may be fused or unfused.
  • Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting).
  • alkanediyl or alkenediyl groups (carbon number limitation permitting).
  • alkyl, aryl, and/or aralkyl groups carbon number limitation permitting attached to the aromatic ring or aromatic ring syste -limiting examples of heteroarenediyl groups include:
  • heteroaryl refers to the compound H-R, wherein R is heteroaryl.
  • Pyridine and quinoline are non-limiting examples of heteroarenes. When these terms are used with the "substituted” modifier one or more hydrogen atom has been independently replaced by -OH,
  • heterocycloalkyl when used without the "substituted” modifier refers to a monovalent non-aromatic group with a carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more non-aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the ring or ring system.
  • heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, oxiranyl, and oxetanyl.
  • N-heterocycloalkyl refers to a heterocycloalkyl group with a nitrogen atom as the point of attachment.
  • heterocycloalkanediyl when used without the “substituted” modifier refers to an divalent cyclic group, with two carbon atoms, two nitrogen atoms, or one carbon atom and one nitrogen atom as the two points of attachment, said atoms forming part of one or more ring structure(s) wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused or unfused.
  • Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting).
  • alkanediyl or alkenediyl groups (carbon number limitation permitting).
  • the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the ring or ring system.
  • the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic.
  • heterocycloalkanediyl groups include:
  • one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -N0 2 , "C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH3, -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , -S(0) 2 NH 2 , or -C(0)OC(CH 3 ) 3 (tert-butyloxycarbonyl, BOC).
  • acyl when used without the “substituted” modifier refers to the group -C(0)R, in which R is a hydrogen, alkyl, aryl, aralkyl or heteroaryl, as those terms are defined above.
  • the groups, -CHO, -C(0)CH 3 (acetyl, Ac), -C(0)CH 2 CH 3 , -C(0)CH 2 CH 2 CH 3 , -C(0)CH(CH 3 ) 2 , -C(0)CH(CH 2 ) 2 , -C(0)C 6 H 5 , -C(0)C 6 H 4 CH 3 , -C(0)CH 2 C 6 H 5 , -C(0)(imidazolyl) are non-limiting examples of acyl groups.
  • a “thioacyl” is defined in an analogous manner, except that the oxygen atom of the group -C(0)R has been replaced with a sulfur atom, -C(S)R.
  • aldehyde corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a -CHO group.
  • one or more hydrogen atom (including a hydrogen atom directly attached the carbonyl or thiocarbonyl group, if any) has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -N0 2 ,
  • the groups, -C(0)CH 2 CF 3 , -C0 2 H (carboxyl), -C0 2 CH 3 (methylcarboxyl), -C0 2 CH 2 CH 3 , -C(0)NH 2 (carbamoyl), and -CON(CH 3 ) 2 are non-limiting examples of substituted acyl groups.
  • alkoxy when used without the "substituted” modifier refers to the group -OR, in which R is an alkyl, as that term is defined above.
  • alkoxy groups include: -OCH 3 (methoxy), -OCH 2 CH 3 (ethoxy), -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 (isopropoxy), -0(CH 3 ) 3 (tert-butoxy), -OCH(CH 2 ) 2 , -O-cyclopentyl, and -O-cyclohexyl.
  • alkenyloxy when used without the “substituted” modifier, refers to groups, defined as -OR, in which R is alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively.
  • alkoxydiyl refers to the divalent group -O-alkanediyl-, -O-alkanediyl-0-, or -alkanediyl-O-alkanediyl-.
  • alkylthio and acylthio when used without the “substituted” modifier refers to the group -SR, in which R is an alkyl and acyl, respectively.
  • alcohol corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group.
  • ether corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group.
  • one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -N0 2 , "C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , or -S(0) 2 NH 2 .
  • alkylamino when used without the "substituted” modifier refers to the group -NHR, in which R is an alkyl, as that term is defined above.
  • alkylamino groups include: -NHCH 3 and -NHCH 2 CH 3 .
  • dialkylamino when used without the "substituted” modifier refers to the group -NRR', in which R and R' can be the same or different alkyl groups, or R and R' can be taken together to represent an alkanediyl.
  • Non-limiting examples of dialkylamino groups include: -N(CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), and N-pyrrolidinyl.
  • dialkylamino groups include: -N(CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), and N-pyrrolidinyl.
  • alkoxyamino refers to groups, defined as -NHR, in which R is alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkylsulfonyl, respectively.
  • a non-limiting example of an arylamino group is -NHC 6 H 5 .
  • a non- limiting example of an amido group is -NHC(0)CH 3 .
  • alkylaminodiyl refers to the divalent group -NH-alkanediyl-, -NH-alkanediyl-NH-, or -alkanediyl-NH-alkanediyl-.
  • alkylsulfonyl and alkylsulfinyl when used without the “substituted” modifier refers to the groups -S(0) 2 R and -S(0)R, respectively, in which R is an alkyl, as that term is defined above.
  • alkenylsulfonyl alkynylsulfonyl
  • arylsulfonyl aralkylsulfonyl
  • heteroarylsulfonyl heteroarylsulfonyl
  • heterocycloalkylsulfonyl are defined in an analogous manner.
  • one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -N0 2 , -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , or -S(0) 2 NH 2 .
  • alkylphosphate when used without the "substituted” modifier refers to the group -OP(0)(OH)(OR), in which R is an alkyl, as that term is defined above.
  • alkylphosphate groups include: -OP(0)(OH)(OMe) and -OP(0)(OH)(OEt).
  • dialkylphosphate when used without the "substituted” modifier refers to the group -OP(0)(OR)(OR'), in which R and R' can be the same or different alkyl groups, or R and R' can be taken together to represent an alkanediyl.
  • Non-limiting examples of dialkylphosphate groups include: -OP(0)(OMe) 2 , -OP(0)(OEt)(OMe) and -OP(0)(OEt) 2 .
  • -OP(0)(OMe) 2 When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, - H 2 , -N0 2 , -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , or -S(0) 2 NH 2 .
  • average molecular weight refers to the weight average molecular weight (Mw) as determined by static light scattering.
  • a "chiral auxiliary” refers to a removable chiral group that is capable of influencing the stereoselectivity of a reaction. Persons of skill in the art are familiar with such compounds, and many are commercially available.
  • a medical response to a therapeutically effective amount may include any one or more of the following: 1) An improvement in the six minute walk test by 5-10 meters, 10-20 meters, 20-30 meters, or greater compared to a baseline study prior to initiation of the therapy; 2) an improvement in World Health Organization functional Class from Class IV to Class III, Class IV to Class II, Class IV to Class I, Class III to Class II, Class III to Class I, or Class II to Class I with the former class being the WHO Class prior to initiation of the therapy; 3) a decrease in mean pulmonary artery pressure by 2-4 mm Hg, 4-6 mm Hg, 6-10 mm Hg or greater compared to a baseline study performed prior to initiation of the therapy; 4) an increase in the cardiac index by 0.05-0.1, 0.1-0.2, 0.2-0.4 liter/min/m 2 or greater compared to baseline study performed prior to initiation of the therapy; 5) an improvement in PVR (i.e., a decrease) by 25-100, 100- 200, 200
  • the time between baseline study prior to initiation of therapy and time of evaluation of efficacy can vary but would typically fall in the range of 4-12 weeks, 12-24 weeks, or 24-52 weeks. Examples of therapeutic efficacy endpoints are given in references McLaughlin et al. (2002), Galie et al.
  • hydrate when used as a modifier to a compound means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecules associated with each compound molecule, such as in solid forms of the compound.
  • IC50 refers to an inhibitory dose which is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical or chemical process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.
  • An "isomer" of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.
  • the term "patient” or “subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof.
  • the patient or subject is a primate.
  • Non- limiting examples of human subjects are adults, juveniles, infants and fetuses.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1 ,2-ethanedisulfonic acid, 2 -hydroxy ethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene- 1 -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinn
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent.
  • Prevention includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.
  • Prodrug means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention.
  • the prodrug itself may or may not also have activity with respect to a given target protein.
  • a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound.
  • esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-P-hydroxynaphthoate, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, -toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like.
  • a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
  • a “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs.
  • “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands.
  • “Diastereomers” are stereoisomers of a given compound that are not enantiomers.
  • Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer.
  • the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds.
  • a molecule can have multiple stereocenters, giving it many stereoisomers.
  • the total number of hypothetically possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters.
  • Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%.
  • enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, 5 * form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures.
  • the phrase "substantially free from other stereoisomers" means that the composition contains ⁇ 15%, more preferably ⁇ 10%, even more preferably ⁇ 5%, or most preferably ⁇ 1% of another stereoisomer(s).
  • Treatment includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.
  • the above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the invention in terms such that one of ordinary skill can appreciate the scope and practice the present invention.
  • BARD can reduce expression of endothelin-1 (ET-1) in mesangial cells (found in the kidney) and endothelial cells (Table 22).
  • BARD also reduced the expression of the vasoconstrictive ET A receptor while increasing the expression of the vasodilatory ETB receptor (Table 22).
  • ET-1 a naturally occurring peptide, is the most potent endogenous vasoconstrictor and has been implicated in the pathogenesis of several cardiovascular diseases. ET-1 can also act as a mitogen and proinflammatory signaling molecule.
  • ET-1 Excessive activity of ET-1 is a source of endothelial dysfunction, in part due to the inhibition of NO signaling (Sud and Black, 2009) and in part due to pro-inflammatory effects (Pernow, 2012).
  • NO signaling Sud and Black, 2009
  • pro-inflammatory effects Pernow, 2012
  • ET-1 signaling is recognized as a potentially attractive therapeutic strategy for certain cardiovascular diseases.
  • Endothelin receptor antagonists have been studied in a number of these diseases, and two are approved for the treatment of pulmonary arterial hypertension.
  • suppression of ET-1 signaling may have adverse consequences in certain patient populations and patients in these groups should be excluded from treatment with agents that counteract ET- 1 signaling.
  • Nrf2 target genes NQOl, SRXN1, GCLC, and GCLM
  • a bardoxolone methyl analog, RTA dh404 was tested in the 5/6 nephrectomy model of chronic renal failure in the rat, a widely-accepted model of hyperfiltration and pressure overload-induced renal injury and failure. Increased oxidative stress and inflammation caused by increased NF- ⁇ and decreased Nrf2 activation in the 5/6 nephrectomy model results in approximately 30% increases in systolic and diastolic blood pressure (Kim, 2010). Moreover, the 5/6 nephrectomy model is associated with intra- and extra-renal hypertension and endothelial dysfunction.
  • Example 2 Effect of RTA dh404 on Lung Histology in a Rat Model of Monocrotaline- Induced Pulmonary Arterial Hypertension
  • MCT monocrotaline
  • PAH pulmonary arterial hypertension
  • MCT is a macro lytic pyrrolizidine alkaloid and is activated to a toxic metabolite (i.e., dehydromonocrotaline) in the liver by cytochrome P450 enzymes, which then induces a syndrome characterized by PAH, pulmonary mononuclear vasculitis, and right ventricular hypertrophy (Gomez-Arroyo et al, 2012).
  • a toxic metabolite i.e., dehydromonocrotaline
  • RTA dh404 male Sprague-Dawley rats received a single injection of MCT on Day 1 and then either vehicle (sesame oil), RTA dh404 (2, 10, or 30 mg/kg/day), or the positive control sildenafil (60 mg/kg/day) for 21 days. Lung tissue was then analyzed by histopathology for arterial hypertrophy, cell infiltrates, and pulmonary edema. Vehicle lungs appeared artifactually more severe because of poor inflation during processing due, in part, to the loss of compliancy from the injury and edema.
  • RTA dh404 inhibited microscopic changes induced from MCT in the lung (i.e., arteriolar hypertrophy, pulmonary edema, and cell and fibrin infiltrates) at all dose level with the 10 mg/kg RTA dh404 dose being as effective as the positive control sildenafil. Pulmonary edema was completely abrogated with the 10 mg/kg/day RTA dh404 treatment and with 60 mg/kg/day of sildenafil (FIG. 18).
  • Part 1 of the study will include both dose-escalation and expansion cohorts.
  • Dose-escalation cohorts will be enrolled one cohort at a time. Each cohort will include the next eight eligible patients randomized using a 3 : 1 assignment ratio to receive bardoxolone methyl or matching placebo to be administered once daily for 16 weeks.
  • the starting dose of bardoxolone methyl will be 2.5 mg with subsequent doses of 5, 10, 20, and 30 mg.
  • PSRC Protocol Safety Review Committee
  • the PSRC will also evaluate data for signs of pharmacodynamic activity and efficacy and may recommend adding expansion cohorts to further characterize safety and efficacy at up to two doses of bardoxolone methyl.
  • Expansion cohorts will be enrolled one cohort at a time and each will include a minimum of 24 patients randomized using a 3: 1 assignment ratio to receive bardoxolone methyl or matching placebo.
  • Two expansion cohorts will be randomized at the doses selected by the PSRC.
  • Expansion cohorts will only be enrolled at the subset of sites selected by the Sponsor for cardiopulmonary exercise testing (CPET) assessments, and CPET assessments will be required for all patients enrolling in the expansion cohorts.
  • CPET cardiopulmonary exercise testing
  • the expansion cohorts may be enrolled in parallel with the dose- escalation cohorts, however, the randomizations of these cohorts will be carried out independently.
  • the size of the expansion cohorts may be increased by up to 10 total patients across both cohorts to ensure at least 24 patients in each cohort have a fully evaluable CPET assessment at baseline for comparison with the Week 16 assessment. Thus, the two expansion cohorts combined will not exceed a total of 58 patients.
  • Part 1 of the study i.e., both dose-escalation and expansion cohorts
  • patients will follow the same visit schedule. Following randomization, patients will be assessed in person during treatment at Weeks 1, 2, 4, 8, 12, and 16 and by telephone contact on Days 3, 10, and 21.
  • Patients who do not enter Part 2 of the study i.e. the extension period), either because they have discontinued taking study drug during Part 1 or have completed the 16- week treatment period as planned but chosen not to continue to Part 2 of the study, will complete an end-of-treatment visit as well as a follow-up visit four weeks after the date of administration of the last dose of study drug.
  • Part 2 (extension period): Patients who discontinue treatment prematurely in study Part 1 are not eligible to continue into study Part 2. All patients from Part 1 who complete the 16-week treatment period as planned will be eligible to continue directly into the extension period to evaluate the intermediate and long-term safety and efficacy of bardoxolone methyl. Day 1 of the extension period will be the same as the Week 16 visit for the treatment period, and patients continuing to the extension period will therefore continue taking study drug at the same dose. Patients randomized to placebo in Part 1 of the study will be assigned to receive bardoxolone methyl at their cohort-specific dose in the extension period.
  • the extension period is planned to continue at least twelve weeks after the last patient enters the extension part of the study.
  • PCWP Pulmonary capillary wedge pressure
  • Pulmonary vascular resistance > 240 dyn.sec/cm 5 or > 3 mm Hg/Liter (L)/minute;
  • PAH therapy consisting of an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type-5 inhibitor (PDE5i).
  • PAH therapy must be at a stable dose for at least 90 days prior to Day 1 ; (amended to include "at least one, but no more than two (2) disease-specific PAH therapies, including endothelin- receptor antagonists (ERAs), riociguat, phosphodiesterase type-5 inhibitors (PDE5i), or prostacyclins (subcutaneous, oral, or inhaled)."
  • vasodilators including calcium channel blockers), digoxin, L-arginine supplementation, or oxygen supplementation;
  • prednisone has maintained a stable dose of ⁇ 20 mg/day (or equivalent dose if other corticosteroid) for at least 30 days prior to Day 1. If receiving treatment for connective tissue disease (CTD) with any other drugs, doses should remain stable for the duration of the study; 11. Had pulmonary function tests (PFTs) within 90 days prior to Day 1 with no evidence of significant parenchymal lung disease per the following criteria:
  • FEV1 Forced expiratory volume in 1 second
  • FEV1/FVC FEV 1/forced vital capacity ratio
  • Total lung capacity > 65% (predicted) must be measured in patients with connective tissue disease
  • V/Q ventilation-perfusion
  • CT spiral/helical/electron beam computed tomography
  • pulmonary angiogram prior to Screening that shows no evidence of thromboembolic disease (i.e. should note normal or low probability for pulmonary embolism). If V/Q scan was abnormal (i.e. results other than normal or low probability), then a confirmatory CT or selective pulmonary angiography must exclude chronic thromboembolic disease;
  • kidney function defined as an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m 2 using the Modification of Diet in Renal Disease (MDRD) 4-variable formula (note: this was subsequently lowered to > 45 mL/min/1.73 m 2 );
  • hepatitis B and/or hepatitis C have a history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication) defined as mild to severe hepatic impairment (Child-Pugh Class A-C); 14. Serum aminotransferase (ALT or AST) levels > the upper limit of normal (ULN) at Screening;
  • bardoxolone methyl (2.5, 5, 10, 20, or 30 mg) or placebo will be administered orally once daily in the morning for 16 weeks.
  • bardoxolone methyl (2.5, 5, 10, 20, or 30 mg) will be administered orally once daily in the morning for the duration of the extension period.
  • a sample size of 8 patients randomized at a 3 : 1 (bardoxolone methykplacebo) assignment ratio in each dose-escalation cohort includes 6 patients treated with bardoxolone methyl for identification of gross safety signals.
  • a small number of patients at each dose is not expected to fully characterize safety, therefore issues of concern identified in only 1 of 6 patients (16%) treated with bardoxolone methyl may suggest the need to collect additional information before escalating the dose, by either adding another cohort at the current dose level or at a lower dose as determined by the PSRC.
  • the objectives of the present study will be to determine the recommended dose range for further study of bardoxolone methyl, to assess the change from baseline in 6-minute walk distance (6MWD) in those patients treated with bardoxolone methyl versus patients given placebo for 16 weeks, and to assess the safety and tolerability of 16 weeks of treatment with bardoxolone methyl versus 16 weeks of administration of placebo
  • Efficacy Changes from baseline in 6-minute walk distance (6MWD) at Week 16; N- terminal pro-B-type natriuretic peptide (NT-Pro BNP); Borg dyspnea index; WHO/NYHA pulmonary arterial hypertension (PAH) functional class (FC); parameters collected during Doppler echocardiography (ECHO), cardiopulmonary exercise testing (CPET), optional cardiac magnetic resonance imaging (MRI), optional near-infrared spectroscopy (MRS) muscle tests, and optional muscle biopsy; and clinical worsening.
  • 6MWD 6-minute walk distance
  • Familial primary pulmonary hypertension (gene PPHl) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am. J. Hum. Genet., 67:737-44,
  • Nrf2 regulatory network provides an interface between redox and intermediary metabolism.
  • Nrf2-Keapl pathway Contribution of impaired Nrf2-Keapl pathway to oxidative stress and inflammation in chronic renal failure.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pulmonology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)
PCT/US2014/052382 2013-08-23 2014-08-22 Methods of treating and preventing endothelial dysfunction using bardoxololone methyl or analogs thereof WO2015027206A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
NZ630951A NZ630951A (en) 2013-08-23 2014-08-22 Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof
MX2016002375A MX2016002375A (es) 2013-08-23 2014-08-22 Métodos de tratamiento y prevencion de la disfunción endotelial utilizando metil bardoxololona o sus análogos.
BR112016003454-6A BR112016003454B1 (pt) 2013-08-23 2014-08-22 Uso de composto de metil bardoxolona
CN201480049377.4A CN105517554B (zh) 2013-08-23 2014-08-22 使用甲基巴多索隆或其类似物治疗和预防内皮功能障碍的方法
IL285832A IL285832B2 (he) 2013-08-23 2014-08-22 שיטות לטיפול ומניעה של תפקדו לקוי של האנדותל בשימוש בברדוקסולון מתיל או באנלוגים שלו
SG11201601202WA SG11201601202WA (en) 2013-08-23 2014-08-22 Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof
EA201690456A EA201690456A1 (ru) 2013-08-23 2014-08-22 Способы лечения и предотвращения эндотелиальной дисфункции с применением бардоксолона метила или его аналогов
MYPI2016000331A MY198522A (en) 2013-08-23 2014-08-22 Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof
EP14789437.2A EP3035937A1 (en) 2013-08-23 2014-08-22 Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof
CA2921386A CA2921386A1 (en) 2013-08-23 2014-08-22 Methods of treating and preventing renal disease using bardoxolone methyl or analogs thereof
JP2016536495A JP6564372B2 (ja) 2013-08-23 2014-08-22 バルドキソロンメチルまたはその類似体を使用して内皮機能障害を処置および予防する方法
KR1020167006597A KR102322057B1 (ko) 2013-08-23 2014-08-22 바독솔론 메틸 또는 이의 유사체를 이용한 내피 기능장애의 치료 및 예방 방법
AU2014308600A AU2014308600B2 (en) 2013-08-23 2014-08-22 Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof
IL244171A IL244171B (he) 2013-08-23 2016-02-17 שיטות לטיפול ומניעה של תפקדו לקוי של האנדותל בשימוש בברדוקסולון מתיל או באנלוגים שלו
IL272242A IL272242B (he) 2013-08-23 2016-02-17 שיטות לטיפול ומניעה של תפקדו לקוי של האנדותל בשימוש בברדוקסולון מתיל או באנלוגים שלו
PH12016500358A PH12016500358A1 (en) 2013-08-23 2016-02-23 Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof
HK16111185.4A HK1223015A1 (zh) 2013-08-23 2016-09-23 使用甲基巴多索隆或其類似物治療和預防內皮功能障礙的方法
AU2020203510A AU2020203510B2 (en) 2013-08-23 2020-05-28 Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361869527P 2013-08-23 2013-08-23
US61/869,527 2013-08-23

Publications (2)

Publication Number Publication Date
WO2015027206A1 true WO2015027206A1 (en) 2015-02-26
WO2015027206A8 WO2015027206A8 (en) 2015-06-11

Family

ID=51794949

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/052382 WO2015027206A1 (en) 2013-08-23 2014-08-22 Methods of treating and preventing endothelial dysfunction using bardoxololone methyl or analogs thereof

Country Status (19)

Country Link
US (3) US20150080465A1 (he)
EP (1) EP3035937A1 (he)
JP (3) JP6564372B2 (he)
KR (1) KR102322057B1 (he)
CN (2) CN105517554B (he)
AU (2) AU2014308600B2 (he)
BR (1) BR112016003454B1 (he)
CA (1) CA2921386A1 (he)
CL (1) CL2016000405A1 (he)
EA (1) EA201690456A1 (he)
HK (1) HK1223015A1 (he)
IL (3) IL285832B2 (he)
MX (2) MX2016002375A (he)
MY (1) MY198522A (he)
NZ (4) NZ774222A (he)
PH (1) PH12016500358A1 (he)
SG (2) SG10201906113RA (he)
TW (2) TWI716341B (he)
WO (1) WO2015027206A1 (he)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9278912B2 (en) 2012-09-10 2016-03-08 Reata Pharmaceuticals, Inc. C13-hydroxy derivatives of oleanolic acid and methods of use thereof
WO2016130927A1 (en) 2015-02-12 2016-08-18 Reata Pharmaceuticals, Inc. Imidazolyl tricyclic enones as antioxidant iflammation modulators
US9556222B2 (en) 2012-06-15 2017-01-31 Reata Pharmaceuticals, Inc. A-ring epoxidized triterpenoid-based anti-inflammation modulators and methods of use thereof
US9593074B2 (en) 2012-09-10 2017-03-14 Reata Pharmaceuticals, Inc. C17-alkanediyl and alkenediyl derivatives of oleanolic acid and methods of use thereof
US9701709B2 (en) 2012-04-27 2017-07-11 Reata Pharmaceuticals, Inc. 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof
US9757359B2 (en) 2008-01-11 2017-09-12 Reata Pharmaceuticals, Inc. Synthetic triterpenoids and methods of use in the treatment of disease
US9796668B2 (en) 2008-04-18 2017-10-24 Reata Pharmaceuticals, Inc. Natural product analogs including an anti-inflammatory cyanoenone pharmacore and methods of use
US9884809B2 (en) 2010-12-17 2018-02-06 Reata Pharmaceuticals, Inc. Pyrazolyl and pyrimidinyl tricyclic enones as antioxidant inflammation modulators
US9889143B2 (en) 2012-09-10 2018-02-13 Reata Pharmaceuticals, Inc. C17-heteroaryl derivatives of oleanolic acid and methods of use thereof
WO2018103766A1 (zh) * 2016-12-07 2018-06-14 广东天键生物科技有限公司 一种化合物、其制备方法及用途
US10093614B2 (en) 2008-04-18 2018-10-09 Reata Pharmaceuticals, Inc. Antioxidant Inflamation modulators: oleanolic acid derivatives with amino and other modifications at C-17
WO2018200692A1 (en) * 2017-04-26 2018-11-01 The Trustees Of The University Of Pennsylvania Methods and systems for virtual and augmented reality training for responding to emergency conditions
US10953020B2 (en) 2016-11-08 2021-03-23 Reata Pharmaceuticals, Inc. Methods of treating Alport syndrome using bardoxolone methyl or analogs thereof
US11117927B2 (en) 2013-04-24 2021-09-14 Abbvie Inc. 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof
WO2021231208A1 (en) * 2020-05-09 2021-11-18 Reata Pharmaceuticals, Inc. Methods of treating covid-19 using bardoxolone methyl or analogs thereof
US11292781B2 (en) 2016-12-16 2022-04-05 Reata Pharmaceuticals, Inc. Pyrimidine tricyclic enone derivatives for inhibition of ROR-gamma and other uses
WO2022126129A1 (en) 2020-12-11 2022-06-16 Reata Pharmaceuticals, Inc. Synthetic triterpenoids for use in therapy
US11584775B2 (en) 2015-09-23 2023-02-21 Reata Pharmaceuticals, Inc. C4-modified oleanolic acid derivatives for inhibition of IL-17 and other uses
US11993574B2 (en) 2019-06-17 2024-05-28 Reata Pharmaceuticals, Inc Pyrazole and imidazole compounds for inhibition of IL-17 and RORgamma

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102322057B1 (ko) * 2013-08-23 2021-11-05 리아타 파마슈티컬즈, 아이엔씨. 바독솔론 메틸 또는 이의 유사체를 이용한 내피 기능장애의 치료 및 예방 방법
US20220017566A1 (en) * 2018-09-28 2022-01-20 Sichuan Haisco Pharmaceutical Co., Ltd. Terpinoid derivatives and uses thereof
WO2020080482A1 (ja) * 2018-10-17 2020-04-23 株式会社 資生堂 血液中のシスタチンｃ量に基づく腎機能検査結果の妥当性を検定する方法
KR20220104734A (ko) * 2019-11-27 2022-07-26 루난 파마슈티컬 그룹 코퍼레이션 올레아난 신남아미드 유도체 및 이의 제조 방법과 용도
AU2020408323A1 (en) 2019-12-16 2022-08-11 Tenax Therapeutics, Inc. Levosimendan for treating pulmonary hypertension with heart failure with preserved ejection fraction (PH-HF-pEF)
CN115697319A (zh) * 2020-04-01 2023-02-03 四川海思科制药有限公司 三萜系化合物nrf2抑制剂的用途
CN111704647B (zh) * 2020-06-15 2021-10-22 中国人民解放军海军军医大学 一类三萜类衍生物及其作为程序性细胞坏死抑制剂的用途
US20220401396A1 (en) * 2021-06-22 2022-12-22 Asklepion Pharmaceuticals, Llc Action of l-citrulline to prevent or treat endothelial dysfunction
CN114097807B (zh) * 2021-11-25 2023-05-05 兰州大学 巴多索隆类化合物在抗农业病原真菌中的用途
CN116509874A (zh) * 2023-02-01 2023-08-01 潍坊医学院附属医院 甲基巴多索隆在制备改善病毒性心肌炎或病毒性心肌损伤的药物中的用途

Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5480792A (en) 1990-09-14 1996-01-02 Biosite Diagnostics, Inc. Antibodies to complexes of ligand receptors and ligands and their utility in ligand-receptor assays
US5525524A (en) 1991-04-10 1996-06-11 Biosite Diagnostics, Inc. Crosstalk inhibitors and their uses
US5631170A (en) 1992-06-10 1997-05-20 Applied Research Systems Ars Holding N.V. Method for improving measurement precision in evanescent wave optical biosensor assays
US5679526A (en) 1989-01-10 1997-10-21 Biosite Diagnostics Incorporated Threshold ligand-receptor assay
US5824799A (en) 1993-09-24 1998-10-20 Biosite Diagnostics Incorporated Hybrid phthalocyanine derivatives and their uses
US5851776A (en) 1991-04-12 1998-12-22 Biosite Diagnostics, Inc. Conjugates and assays for simultaneous detection of multiple ligands
US5885527A (en) 1992-05-21 1999-03-23 Biosite Diagnostics, Inc. Diagnostic devices and apparatus for the controlled movement of reagents without membrances
US5922615A (en) 1990-03-12 1999-07-13 Biosite Diagnostics Incorporated Assay devices comprising a porous capture membrane in fluid-withdrawing contact with a nonabsorbent capillary network
US5939272A (en) 1989-01-10 1999-08-17 Biosite Diagnostics Incorporated Non-competitive threshold ligand-receptor assays
US5947124A (en) 1997-03-11 1999-09-07 Biosite Diagnostics Incorporated Diagnostic for determining the time of a heart attack
US5955377A (en) 1991-02-11 1999-09-21 Biostar, Inc. Methods and kits for the amplification of thin film based assays
US6025395A (en) 1994-04-15 2000-02-15 Duke University Method of preventing or delaying the onset and progression of Alzheimer's disease and related disorders
US6113855A (en) 1996-11-15 2000-09-05 Biosite Diagnostics, Inc. Devices comprising multiple capillarity inducing surfaces
US6143576A (en) 1992-05-21 2000-11-07 Biosite Diagnostics, Inc. Non-porous diagnostic devices for the controlled movement of reagents
US20030232786A1 (en) 2002-01-15 2003-12-18 Tadashi Honda Tricyclic-bis-enone derivatives and methods of use thereof
US20080261985A1 (en) 2006-11-17 2008-10-23 Trustees Of Dartmouth College Synthesis and biological activities of new tricyclic-bis-enones (tbes)
US20090048204A1 (en) 2007-08-15 2009-02-19 Reata Pharmaceuticals, Inc. Novel forms of cddo methyl ester
WO2009146216A2 (en) * 2008-04-18 2009-12-03 Reata Pharmaceuticals. Inc. Antioxidant inflammation modulators: novel derivatives of oleanolic acid
US20090326063A1 (en) 2008-01-11 2009-12-31 Sporn Michael B Synthetic triterpenoids and methods of use in the treatment of disease
US20100041904A1 (en) 2008-04-18 2010-02-18 Xin Jiang Antioxidant inflammation modulators: c-17 homologated oleanolic acid derivatives
US20100048887A1 (en) 2008-04-18 2010-02-25 Eric Anderson Compounds including an anti-inflammatory pharmacore and methods of use
US20100048892A1 (en) 2008-04-18 2010-02-25 Eric Anderson Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at c-17
US20100056777A1 (en) 2008-04-18 2010-03-04 Eric Anderson Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the c-ring
WO2010093944A2 (en) 2009-02-13 2010-08-19 Reata Pharmaceuticals, Inc. Delayed release, oral dosage compositions that contain amorphous cddo-me
US20110201130A1 (en) 2007-05-08 2011-08-18 Abbott Laboratories Human b-type natriuretic peptide assay having reduced cross-reactivity with other peptide forms

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040102361A1 (en) * 2002-11-27 2004-05-27 Frederic Bodin Pharmaceutical composition for the treatment of pulmonary arterial hypertension
CA2563377A1 (en) * 2004-04-23 2005-11-03 Celgene Corporation Methods of using and compositions comprising pde4 modulators for the treatment and management of pulmonary hypertension
EP2558105B1 (en) * 2010-04-12 2019-11-20 Reata Pharmaceuticals, Inc. Bardoxolone methyl for the treatment of obesity
KR102322057B1 (ko) * 2013-08-23 2021-11-05 리아타 파마슈티컬즈, 아이엔씨. 바독솔론 메틸 또는 이의 유사체를 이용한 내피 기능장애의 치료 및 예방 방법
CA3177913A1 (en) * 2020-05-09 2021-11-18 Deborah FERGUSON Methods of treating covid-19 using bardoxolone methyl or analogs thereof

Patent Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5939272A (en) 1989-01-10 1999-08-17 Biosite Diagnostics Incorporated Non-competitive threshold ligand-receptor assays
US5679526A (en) 1989-01-10 1997-10-21 Biosite Diagnostics Incorporated Threshold ligand-receptor assay
US5922615A (en) 1990-03-12 1999-07-13 Biosite Diagnostics Incorporated Assay devices comprising a porous capture membrane in fluid-withdrawing contact with a nonabsorbent capillary network
US5985579A (en) 1990-09-14 1999-11-16 Biosite Diagnostics, Inc. Antibodies to complexes of ligand receptors and ligands and their utility in ligand-receptor assays
US5480792A (en) 1990-09-14 1996-01-02 Biosite Diagnostics, Inc. Antibodies to complexes of ligand receptors and ligands and their utility in ligand-receptor assays
US5955377A (en) 1991-02-11 1999-09-21 Biostar, Inc. Methods and kits for the amplification of thin film based assays
US5525524A (en) 1991-04-10 1996-06-11 Biosite Diagnostics, Inc. Crosstalk inhibitors and their uses
US5851776A (en) 1991-04-12 1998-12-22 Biosite Diagnostics, Inc. Conjugates and assays for simultaneous detection of multiple ligands
US5885527A (en) 1992-05-21 1999-03-23 Biosite Diagnostics, Inc. Diagnostic devices and apparatus for the controlled movement of reagents without membrances
US6143576A (en) 1992-05-21 2000-11-07 Biosite Diagnostics, Inc. Non-porous diagnostic devices for the controlled movement of reagents
US6019944A (en) 1992-05-21 2000-02-01 Biosite Diagnostics, Inc. Diagnostic devices and apparatus for the controlled movement of reagents without membranes
US5631170A (en) 1992-06-10 1997-05-20 Applied Research Systems Ars Holding N.V. Method for improving measurement precision in evanescent wave optical biosensor assays
US5824799A (en) 1993-09-24 1998-10-20 Biosite Diagnostics Incorporated Hybrid phthalocyanine derivatives and their uses
US6025395A (en) 1994-04-15 2000-02-15 Duke University Method of preventing or delaying the onset and progression of Alzheimer's disease and related disorders
US6113855A (en) 1996-11-15 2000-09-05 Biosite Diagnostics, Inc. Devices comprising multiple capillarity inducing surfaces
US5947124A (en) 1997-03-11 1999-09-07 Biosite Diagnostics Incorporated Diagnostic for determining the time of a heart attack
US20030232786A1 (en) 2002-01-15 2003-12-18 Tadashi Honda Tricyclic-bis-enone derivatives and methods of use thereof
US20080261985A1 (en) 2006-11-17 2008-10-23 Trustees Of Dartmouth College Synthesis and biological activities of new tricyclic-bis-enones (tbes)
US20110201130A1 (en) 2007-05-08 2011-08-18 Abbott Laboratories Human b-type natriuretic peptide assay having reduced cross-reactivity with other peptide forms
US20090048204A1 (en) 2007-08-15 2009-02-19 Reata Pharmaceuticals, Inc. Novel forms of cddo methyl ester
WO2009023232A1 (en) 2007-08-15 2009-02-19 Reata Pharmaceuticals, Inc. Novel forms of cddo methyl ester
US20090326063A1 (en) 2008-01-11 2009-12-31 Sporn Michael B Synthetic triterpenoids and methods of use in the treatment of disease
US20100041904A1 (en) 2008-04-18 2010-02-18 Xin Jiang Antioxidant inflammation modulators: c-17 homologated oleanolic acid derivatives
US20100048887A1 (en) 2008-04-18 2010-02-25 Eric Anderson Compounds including an anti-inflammatory pharmacore and methods of use
US20100048892A1 (en) 2008-04-18 2010-02-25 Eric Anderson Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at c-17
US20100048911A1 (en) 2008-04-18 2010-02-25 Xin Jiang Antioxidant inflammation modulators: novel derivatives of oleanolic acid
US20100056777A1 (en) 2008-04-18 2010-03-04 Eric Anderson Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the c-ring
WO2009146216A2 (en) * 2008-04-18 2009-12-03 Reata Pharmaceuticals. Inc. Antioxidant inflammation modulators: novel derivatives of oleanolic acid
WO2010093944A2 (en) 2009-02-13 2010-08-19 Reata Pharmaceuticals, Inc. Delayed release, oral dosage compositions that contain amorphous cddo-me

Non-Patent Citations (53)

* Cited by examiner, † Cited by third party
Title
"The International PPH Consortium, Lane et al., Heterozygous germline mutations in BMPR2, encoding a TGF-b receptor, cause familial primary pulmonary hypertension", NATURE GENETICS, vol. 26, 2000, pages 81 - 84
BADESCH ET AL.: "Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines", CHEST, vol. 126, 2004, pages 35S - 62S
BADESCH: "Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial", ANN. INTERN. MED., vol. 132, 2000, pages 425 - 434
BARST ET AL.: "A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension", N. ENGL. J. MED., vol. 334, 1996, pages 296 - 301
BLANN ET AL., THROMB. HAEMOST., vol. 93, 2005, pages 228 - 235
BOLIGNANO ET AL.: "Pulmonary Hypertension in CKD", AM. J. KIDNEY DIS., vol. 61, 2013, pages 612 - 622, XP029004473, DOI: doi:10.1053/j.ajkd.2012.07.029
DENG: "Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-11 gene", AM. J. HUM. GENET., vol. 67, 2000, pages 737 - 44, XP002909518, DOI: doi:10.1086/303059
DHAUN ET AL.: "Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis", AMERICAN JOURNAL OF PHYSIOLOGY - RENAL PHYSIOLOGY, vol. 296, 2009, pages F 1477 - F 1483
DUMITRASCU ET AL., OXID. MED. CELL. LONGEV., 2013, pages 234631
FORSTERMANN, BIOL. CHEM., vol. 387, 2006, pages 1521 - 1533
GALIE ET AL.: "Ambrisentan therapy for pulmonary arterial hypertension", J. AM. COLL. CARDIOL., vol. 46, 2005, pages 529 - 535, XP027719846
GOLOGANU ET AL., ROM JLNTERN MED., vol. 50, 2012, pages 259 - 68
GOMEZ-ARROYO ET AL.: "The monocrotaline model of pulmonary hypertension in perspective", AM. J. PHYSIOL. LUNG CELL. MOL. PHYSIOL., vol. 302, 2012, pages L363 - L369
GUAZZI; GALIE, EUR. RESPIR. REV., vol. 21, 2012, pages 338 - 346
HANSSON ET AL., ANNU. REV. PATHOL. MECH. DIS., vol. 1, 2006, pages 297 - 329
HAYES; DINKOVA-KOSTOVA: "The Nrf2 regulatory network provides an interface between redox and intermediary metabolism", TRENDS IN BIOCHEM SCI., vol. 39, 2014, pages 199 - 218
HONDA ET AL., BIOORG. MED. CHEM. LETT., vol. 12, 2002, pages 1027 - 1030
HONDA ET AL., J. MED. CHEM., vol. 43, 2000, pages 1866 - 1877
HONDA ET AL., J. MED. CHEM., vol. 43, 2000, pages 4233 - 4246
HOSOKAWA, CARDIOVASCULAR RES., vol. 99, 2013, pages 35 - 43
HUMBERT, NEW ENGL. J. MED., vol. 351, 2004, pages 1425 - 1436
JONES ET AL.: "Activation of thromboxane and prostacyclin receptors elicits opposing effects on vascular smooth muscle cell growth and mitogen-activated protein kinase signaling cascades", MOL. PHARM., vol. 48, 1995, pages 890 - 89
KATAOKA ET AL.: "Oral sildenafil improves primary pulmonary hypertension refractory to epoprostenol", CIRC. J., vol. 69, 2005, pages 461 - 465
KIM; VAZIRI: "Contribution of impaired Nrf2-Keapl pathway to oxidative stress and inflammation in chronic renal failure", AMERICAN JOURNAL OF PHYSIOLOGY - RENAL PHYSIOLOGY, vol. 298, 2010, pages F662 - F671
KOSMADAKIS ET AL., REN. FAIL., vol. 35, 2013, pages 514 - 20
KOTTGEN ET AL.: "Serum cystatin C in the United States: the Third National Health and Nutrition Examination Survey", AM. J. KIDNEY DIS., vol. 51, 2008, pages 385 - 394
LANGLEBEN ET AL.: "STRIDE 1: Effects of the Selective ETA Receptor Antagonist, Sitaxsentan Sodium, in a Patient Population with Pulmonary Arterial Hypertension that meets Traditional Inclusion Criteria of Previous Pulmonary Arterial Hypertension Trials", J. CARDIOVASC. PHARMACAL., vol. 44, 2004, pages S80 - 584.9
LEE ET AL.: "Sildenafil for pulmonary hypertension", ANN. PHARMACOTHER., vol. 39, 2005, pages 869 - 884
MANN ET AL.: "Avosentan for overt diabetic nephropathy", JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, vol. 21, 2010, pages 527 - 535
MARCH'S ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS, AND STRUCTURE, 2007
MCCULLOUGH ET AL: "Cardiac and renal function in patients with type 2 diabetes who have chronic kidney disease; potential effects or bardoxolone methyl.", DRUG DESIGN DEVELOPMENT AND THERAPY, vol. 6, 2012 - 2012, pages 141 - 149, XP002733792 *
MCGOON ET AL.: "Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines", CHEST, vol. 126, 2004, pages 14S - 34S
MCLAUGHLIN ET AL.: "Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension", N. ENGL. J. MED., vol. 338, 1998, pages 273 - 277
MCLAUGHLIN ET AL.: "Survival in primary pulmonary hypertension: the impact of epoprostenol therapy", CIRCULATION, vol. 106, 2002, pages 1477 - 1482
MCLAUGHLIN; RICH: "Pulmonary hypertension", CURR. PROM. CARDIOL., vol. 29, 2004, pages 575 - 634, XP004603550, DOI: doi:10.1016/j.cpcardiol.2004.04.001
OUDIZ: "Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease", CHEST, vol. 126, 2004, pages 420 - 427
P. H. STAHL & C. G. WERMUTH: "Handbook of Pharmaceutical Salts: Properties, and Use", 2002, VERLAG HELVETICA CHIMICA ACTA
PACKER: "Vasodilator therapy for primary pulmonary hypertension. Limitations and hazards", ANN. INTERN. MED., vol. 103, 1985, pages 258 - 270, XP009120531
PAULIN ET AL.: "STAT3 signaling in pulmonary arterial hypertension", JAK-STAT, vol. 1, 2012, pages 223 - 233
PEAKE; WHITING, CLIN. BIOCHEM. REV., vol. 27, 2006, pages 173 - 184
PERGOLA ET AL.: "Bardoxolone methyl and kidney function in CKD with type 2 diabetes.", NEW ENGL. J. MED., vol. 365, 2011, pages 327 - 336, XP055462370, DOI: doi:10.1056/NEJMoa1105351
Q. Q. WU ET AL: "Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPAR , and HO-1", AMERICAN JOURNAL OF PHYSIOLOGY. RENAL PHYSIOLOGY, vol. 300, no. 5, 2 February 2011 (2011-02-02), pages F1180 - F1192, XP055043940, ISSN: 1931-857X, DOI: 10.1152/ajprenal.00353.2010 *
RAWLINS ET AL., AM J. CLIN. PATHOL., vol. 123, 2005, pages 439 - 445
RICH ET AL.: "The effects of high doses of calcium-channel blockers on survival in primary pulmonary hypertension", N. ENGL. J. MED., vol. 327, 1992, pages 76 - 81
RUBIN ET AL.: "Bosentan therapy for pulmonary arterial hypertension", N. ENGL. J. MED., vol. 346, 2002, pages 896 - 903
SCHNEIDER ET AL.: "Contrasting actions of endothelin ETA and ETB receptors in cardiovascular disease", ANNUAL REVIEW OFPHARMACOLOGY AND TOXICOLOGY, vol. 47, 2007, pages 731 - 759
SUSSAN ET AL.: "Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuate cigarette smoke-induced emphysema and cardiac dysfunction in mice", PROC. NATL. ACAD. SCI. US.A., vol. 106, 2009, pages 250 - 255, XP055121341, DOI: doi:10.1073/pnas.0804333106
SUTENDRA; MICHELAKIS: "The metabolic basis of pulmonary arterial hypertension", CELL METABOLISM, vol. 19, 2014, pages 558 - 573
TAM ET AL.: "A derivative of Bardoxolone methyl, dh404, in an inverse dose-dependent manner, lessens diabetes-associated atherosclerosis and improves diabetic kidney disease", DIABETES
THENAPPAN ET AL.: "A USA-based registry for pulmonary arterial hypertension: 1982-2006", EUROPEAN RESPIRATORY JOURNAL, vol. 30, 2007, pages 1103 - 1110
VACHIERY; DAVENPORT: "The endothelin system in pulmonary and renal vasculopathy: les liaisons dangereuses", EUROPEAN RESPIRATORY REVIEW, vol. 18, 2009, pages 260 - 271
VACHIERY; NAEIJE: "Treprostinil for pulmonary hypertension", EXPERT REV. CARDIOVASC. THER., vol. 2, 2004, pages 183 - 191
VASAN: "Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population-based cohort", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 33, 1999, pages 1948 - 1955

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9757359B2 (en) 2008-01-11 2017-09-12 Reata Pharmaceuticals, Inc. Synthetic triterpenoids and methods of use in the treatment of disease
US9796668B2 (en) 2008-04-18 2017-10-24 Reata Pharmaceuticals, Inc. Natural product analogs including an anti-inflammatory cyanoenone pharmacore and methods of use
US11919838B2 (en) 2008-04-18 2024-03-05 Reata Pharmaceuticals Holdings, LLC Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at C-17
US11091430B2 (en) 2008-04-18 2021-08-17 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at c-17
US10556858B2 (en) 2008-04-18 2020-02-11 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at C-17
US10093614B2 (en) 2008-04-18 2018-10-09 Reata Pharmaceuticals, Inc. Antioxidant Inflamation modulators: oleanolic acid derivatives with amino and other modifications at C-17
US11192852B2 (en) 2010-12-17 2021-12-07 Reata Pharmaceuticals, Inc. Pyrazolyl and pyrimidinyl tricyclic enones as antioxidant inflammation modulators
US11814338B2 (en) 2010-12-17 2023-11-14 Reata Pharmaceuticals, Inc. Pyrazolyl and pyrimidinyl tricyclic enones as antioxidant inflammation modulators
US9884809B2 (en) 2010-12-17 2018-02-06 Reata Pharmaceuticals, Inc. Pyrazolyl and pyrimidinyl tricyclic enones as antioxidant inflammation modulators
US9701709B2 (en) 2012-04-27 2017-07-11 Reata Pharmaceuticals, Inc. 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof
US11078230B2 (en) 2012-04-27 2021-08-03 Reata Pharmaceuticals, Inc. 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof
US9556222B2 (en) 2012-06-15 2017-01-31 Reata Pharmaceuticals, Inc. A-ring epoxidized triterpenoid-based anti-inflammation modulators and methods of use thereof
US9889143B2 (en) 2012-09-10 2018-02-13 Reata Pharmaceuticals, Inc. C17-heteroaryl derivatives of oleanolic acid and methods of use thereof
US11406648B2 (en) 2012-09-10 2022-08-09 Reata Pharmaceuticals, Inc. C17-heteroaryl derivatives of oleanolic acid and methods of use thereof
US10501489B2 (en) 2012-09-10 2019-12-10 Reata Pharmaceuticals, Inc. C17-alkanediyl and alkenediyl derivatives of oleanolic acid and methods of use thereof
US9593074B2 (en) 2012-09-10 2017-03-14 Reata Pharmaceuticals, Inc. C17-alkanediyl and alkenediyl derivatives of oleanolic acid and methods of use thereof
US10898499B2 (en) 2012-09-10 2021-01-26 Reata Pharmaceuticals, Inc. C17-heteroaryl derivatives of oleanolic acid and methods of use thereof
US9278912B2 (en) 2012-09-10 2016-03-08 Reata Pharmaceuticals, Inc. C13-hydroxy derivatives of oleanolic acid and methods of use thereof
US11117927B2 (en) 2013-04-24 2021-09-14 Abbvie Inc. 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof
US11873320B2 (en) 2013-04-24 2024-01-16 Reata Pharmaceuticals Holdings, LLC 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof
US11059792B2 (en) 2015-02-12 2021-07-13 Reata Pharmaceuticals, Inc. Imidazolyl tricyclic enones as antioxidant inflammation modulators
WO2016130927A1 (en) 2015-02-12 2016-08-18 Reata Pharmaceuticals, Inc. Imidazolyl tricyclic enones as antioxidant iflammation modulators
US11584775B2 (en) 2015-09-23 2023-02-21 Reata Pharmaceuticals, Inc. C4-modified oleanolic acid derivatives for inhibition of IL-17 and other uses
US10953020B2 (en) 2016-11-08 2021-03-23 Reata Pharmaceuticals, Inc. Methods of treating Alport syndrome using bardoxolone methyl or analogs thereof
US11446313B2 (en) 2016-11-08 2022-09-20 Reata Pharmaceuticals Holdings, LLC Methods of treating Alport syndrome using bardoxolone methyl or analogs thereof
WO2018103766A1 (zh) * 2016-12-07 2018-06-14 广东天键生物科技有限公司 一种化合物、其制备方法及用途
US11292781B2 (en) 2016-12-16 2022-04-05 Reata Pharmaceuticals, Inc. Pyrimidine tricyclic enone derivatives for inhibition of ROR-gamma and other uses
WO2018200692A1 (en) * 2017-04-26 2018-11-01 The Trustees Of The University Of Pennsylvania Methods and systems for virtual and augmented reality training for responding to emergency conditions
US11993574B2 (en) 2019-06-17 2024-05-28 Reata Pharmaceuticals, Inc Pyrazole and imidazole compounds for inhibition of IL-17 and RORgamma
WO2021231208A1 (en) * 2020-05-09 2021-11-18 Reata Pharmaceuticals, Inc. Methods of treating covid-19 using bardoxolone methyl or analogs thereof
WO2022126129A1 (en) 2020-12-11 2022-06-16 Reata Pharmaceuticals, Inc. Synthetic triterpenoids for use in therapy

Also Published As

Publication number Publication date
WO2015027206A8 (en) 2015-06-11
CN105517554B (zh) 2021-01-15
HK1223015A1 (zh) 2017-07-21
AU2014308600A1 (en) 2016-03-03
TW202026003A (zh) 2020-07-16
MY198522A (en) 2023-09-04
CA2921386A1 (en) 2015-02-26
US20190091194A1 (en) 2019-03-28
CN105517554A (zh) 2016-04-20
AU2020203510A1 (en) 2020-06-18
IL285832B1 (he) 2023-09-01
TWI716341B (zh) 2021-01-21
IL272242B (he) 2021-09-30
SG10201906113RA (en) 2019-08-27
KR102322057B1 (ko) 2021-11-05
AU2014308600B2 (en) 2020-03-05
TW201542211A (zh) 2015-11-16
TWI717026B (zh) 2021-01-21
NZ744036A (en) 2020-09-25
CL2016000405A1 (es) 2017-02-24
NZ774222A (en) 2023-01-27
SG11201601202WA (en) 2016-03-30
IL272242A (he) 2020-02-27
IL285832A (en) 2021-09-30
BR112016003454A2 (pt) 2017-08-01
MX2021002897A (es) 2021-06-08
MX2016002375A (es) 2016-12-20
US20150080465A1 (en) 2015-03-19
EP3035937A1 (en) 2016-06-29
JP2019131599A (ja) 2019-08-08
US20240115542A1 (en) 2024-04-11
JP6564372B2 (ja) 2019-08-21
JP6701407B2 (ja) 2020-05-27
KR20160061994A (ko) 2016-06-01
NZ756256A (en) 2021-07-30
IL244171A0 (he) 2016-04-21
PH12016500358A1 (en) 2016-05-16
JP2019048873A (ja) 2019-03-28
IL285832B2 (he) 2024-01-01
BR112016003454B1 (pt) 2023-02-14
NZ630951A (en) 2018-09-28
JP2016528300A (ja) 2016-09-15
AU2020203510B2 (en) 2023-05-11
CN112870202A (zh) 2021-06-01
JP6526306B2 (ja) 2019-06-05
IL244171B (he) 2020-02-27
EA201690456A1 (ru) 2016-06-30

Similar Documents

Publication Publication Date Title
AU2020203510B2 (en) Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof
AU2017356955B2 (en) Methods of treating Alport syndrome using bardoxolone methyl or analogs thereof
JP2007520542A (ja) ボリコナゾールおよび抗真菌性ｃｙｐ２ｃ１９阻害薬の組合わせ
EA042085B1 (ru) Способ лечения и предотвращения заболевания почек
JP7421815B2 (ja) 心不全の治療のための１７ベータ－複素環ジギタリス類似化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14789437

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2921386

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 244171

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2016536495

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 12016500358

Country of ref document: PH

Ref document number: MX/A/2016/002375

Country of ref document: MX

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112016003454

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2014308600

Country of ref document: AU

Date of ref document: 20140822

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20167006597

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2014789437

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 201690456

Country of ref document: EA

ENP Entry into the national phase

Ref document number: 112016003454

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20160218